Preparation of 17&#39; -propadienyl steroids

ABSTRACT

Disclosed is a process for the preparation of 17 Alpha propadienyl steroids of the estrogen, estrane, and androstane series which contain optional substitution at other positions of the nucleus. This process involves treating a corresponding 3(substituted propynyl) steroid wherein the substituent is halo, alkylsulfonyloxy, arylsulfonyloxy, tetrahydrofuran-2-yloxy, tetrahydropyran-2-yloxy, or 4-methoxytetrahydropyran-4-yloxy, with an aluminum hydride reagent in organic reaction media. The product 17 Alpha -propadienyl steroids in the Delta 5(10),9(11)estradiene and Delta 4,9(10),11-estratriene series, optionally substituted at the C-3, C-17, and C-18 positions, are new compounds. Certain of the 17 Alpha -(3-substituted propynyl) compounds hereof are new compounds, useful as intermediates. The 17 Alpha -propadienyl products are useful as estrogenic, antiandrogenic, progestational and anti-fertility agents.

[4 1 Sept. 9, 1975 1 i PREPARATION OF l7oz-PROPADIENYL STEROIDS [75] Inventor: John J. Edwards, Los Altos, Calif.

[73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Feb. ll, 1974 121] Appl. No.: 441,223

Related US. Application Data [63] Continuation-in-part of Ser. No. 297,855, Oct. 16, 1972, which is a continuation-in-part of Ser. No. 148,174, May 28, 1971, which is a continuation-in-part of Ser. No. 877,521, Nov. 17, 1969, abandoned, which is a continuation-in-part of Scr. No. 817,563, April 18, 1969, abandoned,

[52] US. Cl. 260/239.55C; 260/397.45; 260/397.45;

260/3974; 260/3975; 424/243 [51] Int. Cl. C07,] 17/00 [58] Field of Search... 260/239.55 R, 397.4, 397.45

[56] References Cited UNITED STATES PATENTS 3,392,165 7/1968 Edwards ct al. 260/239.55

7/1968 Edwards et al. 260/239.55 3/1974 Galantay ct al 260/239.55 C

Primary ExaminerElbert L. Roberts Attorney, Agent, or FirmGerard A. Blaufarb; Walter H. Dreger; William B. Walker [57] ABSTRACT Disclosed is a process for the preparation of 17apropadienyl steroids of the estrogen, estrane, and androstane series which contain optional substitution at other positions of the nucleus. This process involves treating a corresponding 3-(substituted propynyl) steroid wherein the substituent is halo, alkylsulfonyloxy, arylsulfonyloxy, tetrahydrofuran-Z-yloxy, tetrahydropyran-Z-yloxy, or 4-methoxytetrahydropyran-4-yloxy, with an aluminum hydride reagent in organic reaction media. The product 17a-propadienyl steroids in the A (10),9(1l)-estradiene and A ,9(lO),l l-estratriene series, optionally substituted at the C-3, C-l7, and C-l8 positions, are new compounds. Certain of the l7a-(3-substituted propynyl) compounds hereof are new compounds, useful as intermediates. The 17apropadienyl products are useful as estrogenic, antiandrogenic, progestational and anti-fertility agents.

23 Claims, No Drawings PREPARATION OF l7a-PROPADIENYL STEROIDS This application is a continuation-in-part of application Ser, No. 297,855, filed Oct. 16, 1972, which is a continuation-in-part of application Ser. No. 148,174, filed May 28, 1971, which is a continuation-in-part of application Scr. No, 877,521, filed Nov, 17, 1969, now abandoned, which is a continuation-in-part of application Ser. No. 817,563, filed Apr. 18, 1969, now abandoned.

process useful in preparing steroidal l7a-allcnes.

Certain of the steroid compounds which have a 1711- ethylenically unsaturated side chain, specifically a 1704- propadienyl (allene) grouping, are novel, particularly those 17ozpropadienyl steroids of the 6,6-difluoro series and those l7apropadienyl steroids of the A'""" series and those 17a-propadienyl steroids of the A""" series, represented respectively by the Formulas (A), (B), and (C):

Other l7a-propadienyl steroids have been described. For example, US. Pat. Nos. 3,392,165 and 3,392,166

The present invention relates to a novel process 40 disclose, inter alia, those derivatives of the estrogen,

which is useful in the preparation of useful steroidal compounds. Specifically, this invention is directed to a estr-4-ene, estr-5(10)-ene and androst4-ene series as represented by Formulas (I1), (111), and (IV):

R1 2 OR .cn-e-cn (III) R 2 OR 2l ...CH=C=CH Other useful l7a-propadienyl steroids can be represented by the following formula:

. CH=C=CH In the above and succeeding formulas, R is hydrogen or lower alkyl of from 1 to 3 carbon atoms, inclusive; R is hydrogen, tetrahydrofuran-Z-yl, tetrahydropyran- 2-yl, 4-methoxytetrahydropyran-4-yl, or a carboxylic acyl group containing less than 12 carbon atoms; R is an oxo group or the group ner such agents are customarily used for the treatment of conditions responsive to estrogenic and antiandrogenic agents, such as the control and regulation of fertility and the treatment of acne, benign prostate hypertrophy, and hirsutism in females. The l7a-propadienyl derivatives in the 6,6-difluoroandrostene, 6,6-difluorol9-norandrostene, estr-5(10)-ene, estr-4-ene, androst- 4-ene, and estra-4,9( l0)-diene series (Formulas A, II, IV, and V demonstrate progestational and pituitary inhibiting and anti-fertility activity and are useful in the manner corresponding to such activity such as in the treatment of various menstrual disorders and in the control and regulation of fertility.

The l7a-propadienyl compounds in the estratriene and A ""-""-estradiene series (Formulas B and C) also demonstrate progestational, pituitary in- When operating in accordance with preferred embodiments, the present invention is particularly useful for the preparation of the 17a-propadienyl steroids of the estrogen, estrane, and androstane series depicted above in Formulas (A), (B), (C), (II), (III), (IV), and (V).

Suitable aluminum hydride reagents include those containing at least two available hydrogen atoms such as aluminum hydride, lithium aluminum hydride, lithium di-(2methoxyethoxy)-aluminum hydride, lithium diisobutylaluminum hydride, and sodium aluminum hydride.

The aluminum hydride reagent is conveniently employed in at least chemical equivalent amounts with the steroid starting material. Amounts in excess of this, upwards of a 20 to 50 molar excess, can also conveniently be employed. Preferred embodiments involve the use of from about 1.5 moles to 20 moles of aluminum hydride reagent per mole of starting steroid.

The reaction is conducted in the presence of organic liquid reaction medium. Suitable media include the customary organic solvents, for example, ethers, such as dimethyl ether, dioxane, methyl propyl ether, tetrahydrofuran, and the like; saturated aliphatic hydrocarbons, such as pentane, hexane, 'octane, and the like; and aromatic hydrocarbons, such as benzene, toluene, mesitylene, and the like.

The reaction is conducted at temperatures ranging from about 20 to about C. and preferably at the boiling point of the reaction mixture and under reflux. The reaction is continued for a period of time sufficient to complete the reaction ranging from about 2 hours to about 48 hours. Longer or shorter periods may be employed depending upon the choice of reaction temperature and reactants employed.

In a preferred procedure, the starting steroid compound, dispersed in an organic liquid reaction medium, is treated with aluminum hydride reagent on at least a mole per mole basis. The resulting reaction mixture is then heated with stirring for a sustained period of time. Upon completion of the reaction, the respective product is separated and recovered from the reaction mixture via conventional techniques such as filtration, decantation, evaporation, chromatography, recrystallization, and the like.

Certain of the l7oz-(3-substituted propynyl) compounds, useful as herein described, are novel compounds and can be represented as follows:

(VIII) in which R is hydrogen, tetrahydrofuran-Z-yl, tetrahydropyran-Zyl, 4-methoxytetrahydropyran-4-yl, or a carboxylic acyl group containing less than 12 carbon atoms;

R is hydrogen or methyl;

R is hydrogen, lower alkyl of from I to 8 carbon atoms, inclusive, cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl or a carboxylic acyl group containing less than I2 carbon atoms; and

each Z is a carbon-carbon single bond or a carboncarbon double bond;

and the C-3 ketals of the compounds of formulas (VI), (VII) and (IX) and the C-3 enol ethers of the compounds of formula (VI). Particularly important compounds selected from those depicted above are those wherein R is tetrahydropyran-Z-yloxy or chloro and those thereof of Formulas (VI) and (VII).

As starting compounds, the tetrahydrofuran-Z-yloxy, tetrahydropyran-2-yloxy, and 4-methoxytetrahydropyran-4-yloxy ethers of the l7a-( 3-hydroxypropynyl) steroid compounds are prepared by treating the corresponding l7-oxo steroid with the Grignard reagent prepared upon treatment of the reaction product of propargyl alcohol and dihydrofuran, dihydropyran, and 4- methoxy-S,6-dihydro-2H-pyran (3-tetrahydrofuran2 yloxypropyne, 3-tetrahydropyran-2-yloxypropyne, and 3-(4-methoxytetrahydropyran-4-yloxy)propyne, respectively) with ethyl magnesium bromide in the manner known per sev In this manner, the corresponding l7a-( 3-tetrahydrofuran-2-yloxypropynyl l7a-( 3- tetrahydropyran-2'yloxypropynyl), and l7a-(3-(4'- methoxytetrahydropyran-4'-yloxy)propynyl) steroid starting compounds are prepared.

The starting steroid compounds of the present invention which contain a l7oz-(3-halopropynyl) grouping are prepared from the corresponding l7a-(3-hydroxypropynyl) compounds which are obtained from the ethers thereof (prepared as described above) upon conventional hydrolysis, such as with a mineral or organic acid. This halogenation-replacement conversion is accomplished in the bromo and chloro series by treatment of the hydroxy compound with thionyl bromide or phosphorus pentabromide or with thionyl chloride or phosphorus pentachloride in the presence of a tertiary amine base, such as the tertiary alkyl amines, pyridine, lutidine, and so forth. The reaction is carried out in any convenient order or fashion and at temperatures of from about 0 to about 20C. and, conveniently, in organic liquid reaction medium, such as ether, benzene, and the like. See Preparation 19 hereof for preparation of the iodo compounds. Alternatively, the bromo and chloro derivatives can be prepared by treating the hydroxy compound with triphenylphosphine and carbon tetrabromide or carbon tetrachloride in organic reaction medium, such as dimethylformamide and dioxane, at about I 10C. for a few minutes followed by the usual recovery procedures.

In the fluoro series, the hydroxy compound is treated with a hydrocarbon sulfonyl fluoride including benzyl sulfonyl fluoride, tosyl fluoride and mesyl fluoride. This process also preferably employs an inert hydrocarbon solvent, such as hexane, heptane, benzene, toluene or an esterified or etherified alcohol, such as dimethoxyglycol. Other suitable solvents are chloroform and nitromethane. The reaction is carried out at temperatures of from 0 to about C. for from one to about eight hours.

Alternatively, the 3-fluoropropynyl compounds are prepared by treating the 3-hydroxypropynyl compounds with l-diethylamino- 1 ,1 ,2-trifluoro-2- chloroethane in methylene chloride, acctonitrile, diethyl ether, dioxane, tetrahydrofuran, and the like, in the method known per se. see US. Pat. No. 3,444,188, for example.

The l7a-(3-arylsulfonyloxypropynyl) and l7a-( 3 alkylsulfonyloxypropynyl) starting compounds hereof are likewise prepared from the l7a-(3- hydroxypropnyl) compounds upon treatment of the latter with an arylsulfonyl chloride or alkylsulfonyl chloride, respectively. This reaction is conveniently conducted in pyridine and at or about room temperature. Suitable arylsulfonyl chlorides for this purpose include 4-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 1 4- chlorobenzenesulfonyl chloride, 2-nitro-4- chlorobenzenesulfonyl chloride, mesitylenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2- naphthalenesulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, and the like. Suitable alkylsulfonyl chlorides include methanesulfonyl chloride, 3- chloropropanesulfonyl chloride, l-hexadecanesulfonyl chloride, and the like.

The l7a-(3-hydroxypropynyl) steroid compound from which the 3-halopropynyl derivatives are prepared are, in turn, prepared via several methods. In one such method, Grignard reagent is prepared upon treatment of the product of the reaction of propargyl alcohol and dihydropyran 3 tetrahydropy ran-2 yloxypropyne), with magnesium and ethyl bromide in the method known per se. This reagent is then reacted with a l7-oxo steroid. In this manner, the corresponding l7a-(3-tetrahydropyran-2'-yloxypropynyl) steroidal derivative is prepared. Thereafter, the thus formed derivative is conventionally hydrolyzed such as with a mineral or organic acid to hydrolyze the tetrahydropyran-2'-yloxy group forming the hydroxyl.

An alternative method for the preparation of the 3- hydroxy propynyl compounds hereof, which method is particularly useful in the estrogen series, involves ethynylating a l7-oxo starting compound via the method known per se, that is, through treatment with potassium acetylide to give the l7a-ethynyl-l7/3- hydroxy derivative. Thereafter, the l7,8-hydroxy group is preferably protected before further reaction, such as by forming the tetrahydropyran-Z-yloxy or tetrahydrofuran-2-yloxy ether thereof. In such further reaction, the ethynyl group is elaborated as respect the addition of the hydroxymethyl group as a replacement for the acidic hydrogen. This is accomplished by forming the ethyny] lithium salt (by treating the ethynyl derivative at room temperature with an equivalent amount of an ether solution of methyl, butyl, or phenyl lithium) and treating this with an equivalent or slight excess amount of paraformaldehyde at gentle reflux in ether followed by hydrolysis, all in accordance with the procedures described by Schaap et al., in Rec. Trav. Chim. 84, 1200 1965 as well as the references cited therein.

The procedures for preparing the starting 3- halopropynyl steroids hereof are more completely described in, for example, US. Pat. No. 3,029,261.

In the preparation of the starting l7a-(3-substituted propynyl) derivatives in the 6,6-difluoroandrostene and 19-nor-androstene series, the foregoing preparations can be practiced upon the corresponding 6,6- difluoroandrost-4-ene-3,17-diones and 6,6-difluorol9-norandrost-4-ene-3,l7-diones and the l8-alkyl derivatives thereof. In practice, the 6,6-difluoro grouping is introduced into the precursor androst-4-ene-3,17- diones and l9-norandrost-4-ene3,l7-diones or 18- alkyl derivatives thereof. One method by which this is done is described in US. ,Pat. No. 3,2l9,673. This method involves treating a 3-acyloxy5-fluoro-6-keto steroid (which are known or can be prepared as described in the cited patent and its references) with sulfur tetrafluoride to prepare the corresponding 3- acyloxy-5,6,6-trifluoro steroid which is hydrolyzed to the 3-hydroxy-5,6,6-trifluoro compound. The latter compound is oxidized to the corresponding 3-keto- 5,6,6-trifluoro derivative which is then treated with a dehydrofluorinating agent such as alumina to provide the 3-keto-A*-6,6-difluoro compound.

Another method by which these 6,6-difluoro steroids are prepared involves twice consecutively forming an enol ether and treating this with perchloryl fluoride. Thus, the starting androst-4-ene-3,l7-clione is converted to its enol ether and it is treated with perchloryl fluoride to form the 3-ketoA*-6-fluoro derivative. The same procedure is followed with this compound to form the 3-keto-A*-6,6-difluoro products.

The starting l7a-(3-substituted propynyl) compounds in the A""-estradiene, A ""-estradiene, and N -eStratriene series are prepared from the corresponding l7-oxo compounds as described above. The A -estratrienel 7-one compounds are known and can be prepared by treating a 3-keto-A steroid with bromine in pyridine solution to form the corresponding 3-keto-A '-diene, ketalizing the resulting diene to the corresponding 3-ketal-A """-diene, epoxidizing this ketal diene with a peroxy acid, and treating the epoxidized product with strong acid.

Alternatively, a 3-keto-A is treated with hydrogen chloride in methanol at room temperature to obtain the corresponding 3,3-dimethoxy-A compound which is hydrolyzed to give the 3-keto-A compound. This compound-is then converted to the 3- keto-N' and thence to the Ia-keto-N compound as described above. See Steroids 8: l p. 87 (July 1966) and US. Pat. Nos. 3,282,785 and 3,46l,l 18, the subject matter of which is hereby incorporated by reference. The l7-oxo compounds in the N A and A'' series are reduced such as with lithium trit-butoxy aluminum hydride to form the 3,17-diol. This is acylated and the 3-acylate-l7-ol separated by chromatography. The l7-alcohol is then oxidized such as with chromic acid to provide the l7-one compound which is elaborated as described above.

Alternatively, the 3-keto-l7B-ol compound can be protected by formation of the 3,3-ketal followed by oxidation of the 17,8-0], with Collins reagent.

in the preferred embodiments, the desired noninterfering elaborative groupings at the other optional sites of the molecule are introduced prior to the novel, principal reaction hereof. Protection is preferably provided for those groups which may compete or interfere with the principal reaction hereof or with the processes preparative to the principal reaction hereof. Examples of such protection include forming the ketal or enol ethers of the 3-oxo functions which can be restored later in the synthetic sequence. Alternatively, and in the preferred embodiments, the 3-keto function is left unprotected and the resultant 3B-hydroxy is backoxidized. such as with chromic acid in pyridine, manganese dioxide, etc. In the preferred embodiments, the

principal reaction hereof is performed upon the 17,8- hydroxy (or an ester thereof) starting compounds.

In the estrogen series, treatment of, for example, the l7oz-ethynyl-3,l7B-diol derivative with an appropriate carboxylic acid anhydride, such as acetic anhydride, in pyridine yields the 3-acyloxy-l7B-hydroxy derivative selectively. Use of an acid anhydride in the presence of the corresponding acid and an acid catalyst, such as p-tolucnesulfonic acid yields the 3,17,8-diacyloxy derivative. This diester may then be selectively saponified as through the use of methanolic potassium bicarbonate to yield the corresponding 3hydroxy-l7,8-acyloxy derivative. Similarly, etherification may be performed via the conventional procedures. Thus, treatment with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid, p-toluenesulfonyl chloride, dinitrobenzenesulfonic acid, or the like, yields the corresponding tetrahydropyran-2-yloxy derivative. Formation of the mono-tetrahydropyranyl ether may be accomplished by selective protection of other hydroxy groups as through ester formation, in the manner described above, with alkaline hydrolysis of such ester groups after formation of the ether, if desired. Formation of B-methoxy derivatives may likewise be realized through the use of dimethylsulfate and potassium hydroxide in the conventional manner.

Similar conventional esterification and etherification procedures can be employed in the other series of starting compounds for the present invention. For example, in the preparation of the 3,8,17,8-diacylate starting materials for the process hereof, the 3,17-dioxo compound can be reduced and acylated with about one chemical equivalent of acylating agent. The product mixture is then chromatographed to separate the 3B- acylate-l7B-ol compound. This derivative is then oxidized to the 3B-acylate-l7-oxo compound. The Grignard method of introducing the etherified propynyl group at C-l7a, as described above, is then followed including the addition of the appropriate acylating before work-up to form the 3B,] 7B-diacylate-l7aetherified propynyl compound. These compounds are utilized as starting compounds or are converted to the other l7oz-(3-substituted propynyl) starting compounds hereof.

The 3,8,l7B-diethers can be conveniently formed by initially preparing the 3B,17B-diethers and following this with the formaldehyde method of preparing the 17a-( hydroxy-propynyl) compounds, as described above. These compounds can then be etherified with dihydrofuran, dihydropyran, or 4-methoxy-5,6- dihydro-2H-pyran.

If a mixed ester-ether compound is desired, the monoether is prepared in a sequence similar to that used for preparing the mono-acylate. Thereafter, the described Grignard method is followed ending with an acylation before work-up. Alternatively, the mono acylate, prepared as described above, can be ethynylated at C-l7oz and the C-l7B hydroxyl etherefied. Thereafter, the described formaldehyde method is employed for the preparation of the corresponding l7a-( hydroxypropynyl) compound which can be etherified as described above.

In the present specification and claims, the term carboxylic acyl group and carboxylic acyloxy group denote acyl and acyloxy groups which contain less than 12 carbon atoms and which can be of a straight, branched, or cyclic chain structure. This structure can further be saturated, unsaturated or aromatic and optionally substituted by functional groups, such as hydroxy, alkoxy containing up to five carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Representative esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, ,B-chloropropionate, adamantoate, bicyclo[ 2.2.2] octanel carboxylate, bicyclo[ 2.2.2 loct 2-enel-carboxylate, 4-methylbicyclo[2.2.21oct-2-enel-carboxylate, and so forth. The lower alkyl group in the present specification and claims can be of straight or branched chain structure. Representative alkyl groups include methyl, ethyl, isopropyl, n-butyl, t-butyl, n-hexyl, n'heptyl, noctyl, isooctyl, and the like. in the present specification and claims, the term cycloalkyl group which is represented above by R include, for example, eyclopentyl, cyclohexyl, and the like, and in general, contain from three to eight carbon atoms. In the present specification and claims, the term 3-halopropynyl" includes 3-bromopropynyl, 3-chloropropynyl, and 3- iodopropynyl, and 3-fluoropropynyl, preferably 3- chloropropynyl.

The alkylsulfonyloxy grouping hereof is one wherein the alkyl group is as defined above, preferably containing from 1 to 6 carbon atoms inclusive. The alkyl group can also be substituted, notably with halogen. Thc arylsulfonyloxy grouping hereof is one wherein the aryl group is naphthyl, phenyl or a mono or poly substituted phenyl, the substituents being se lected from alkyl, alkoxy, halogeno, nitro, and the like.

The following preparations and examples serve to further illustrate the manner by which the present in vention can be practiced. As such, however, they should not be construed as limitations upon the overall scope hereof.

Preparation 1 A solution is prepared by dispersing 29 grams of estr- 4-ene-3,l7dione in 600 ml. of dioxane at room temperature with stirring. Ethyl orthoformate ml) and 1.8 grams of p-toluenesulfonic acid hydrate are added to the resultant mixture. The addition is conducted portionwise with stirring, and at room temperature. After the addition is complete, the resulting reaction mixture is allowed to stand at room temperature for three and one half hours. After this time, the resulting solution is poured into two liters of ice water. After this has been accomplished, the whole mixture is filtered to yield a crystalline material which is recrystallized from methy lene chloride: methanol containing a few drops of pyridine to obtain the desired 3-ethoxyestra-3,5-dienl7-one product.

Propargyl alcohol (42 grams) is dispersed in 63 grams of 2,3-dihydropyran with stirring. While continuing the stirring at room temperature, phosphorus oxychloride (500 mg) is added portionwise to the resultant solution. The reaction mixture rapidly becomes warm and is cooled intermitently in ice. After maintaining these conditions for two hours and then allowing the temperature of the reaction mixture of stabilize at room temperature, an aqueous solution of potassium hydroxide is added. The mixture is then extracted with ether and the ether extracts distilled under gradually increasing temperatures and gradually decreasing pressures to obtain the 3-tetrahydropyran-2'-yloxypropyne product.

The corresponding 3-tetrahydrofuran-2'- yloxypropyne and 3-(4'-methoxytctrahydropyran-4'- yloxy)propyne products are similarly prepared upon substitution of 2,3-dihydrofuran and 4-methoxy-5bdihydro-ZH-pyran for 2,3-dihydropyran.

To 12 g. of tetrahydropyran-2-yloxypropyne are added 100 ml. of anhydrous tetrahydrofuran and 35 ml. of ethyl magnesium bromide. The reaction mixture is refluxed for 5 minutes and left at room temperature for 2 hours. Then, g. of 3-ethoxyestra-3,5-dien-l7-one in 150 ml. of anhydrous tetrahydrofuran are added, and the reaction mixture is kept at room temperature for 2 hours. 'It is then poured into a saturated ammonium chloride solution and extracted with methylene chloride, washed with water, dried and evaporated to dryness to yield 3-ethoxy-l70z-(3-tetrahydropyran-2'- yloxypropynyl )-estra-3 ,S-dienl 7,Bol.

In like manner are prepared 3-ethoxy-l7a-(3- tetrahydrofuran-2'-yloxypropynyl )-estra-3 ,S-dienl 7,8- 01, and 3-ethoxy-l 7cx-(3-(4'methoxytetrahydropyran- 4'-yloxy )propynyl )-estra-3,5-dienl 7B-ol. The foregoing can be similarly practiced upon the other compounds of this invention to prepare the corresponding l7a-( 3-tetrahydrofuran-2 -yloxypropynyl l 701-(3- tetrahydropyran-Z'-yloxypropynyl), and l7a(3-(4- methoxytetrahydropyran-4-yloxy)propynyl starting compounds hereof.

If, after the reaction period above described, the reaction mixture is cooled in ice water and then mixed with 50 ml. of acetic anhydride and left at room temperature for 16 hours followed by the work-up as described, a l7oz-(3-tetrahydropyran-2'-yloxypropynyl)- l7B-acetoxyestr-4-en-3-one is prepared.

Under anhydrous conditions, 3.2 g. of magnesium, l 1 ml. of ethyl bromide, and 150 ml. of absolute ether are mixed together at room temperature. To the resulting solution is added, dropwise and at room temperature, 30 g. of 3-tetrahydropyran-2-yloxypropyne product obtained as described above. The temperature of the resulting mixture is heated to the boiling point and maintained under reflux conditions for 5 minutes. After this time, the mixture is cooled to room temperature and mixed dropwise with a solution containing 21 grams of 3-ethoxy-estra-3,5-dien-l7-one which is dispersed in 200 ml. of tetrahydrofuran. After this addition is complete, the reaction mixture is stirred at room temperature for a period of two hours. The resulting solution is cooled in an icebath and then mixed with 70 ml. of acetic anhydride. This solution is then left at room temperature for 16 hours. After this, the mixture is poured into an ammonium chloridezice solution and this is then extracted with ether, the ether extracts being dried and evaporated to a concentrated form. The concentrate is chromatographed to obtain a crystalline product which is crystallized from ethyl acetate:- hexanezpetroleum ether. Recrystallization from the same solvent mixtures obtains the desired l7a-(3- tetrahydropyran-Z -yloxypropynyl l 7B-acetoxyestr-4- en-3-0ne product.

Preparation 2 3-Ethoxyl7oz-( 3-tetrahydropyran-2 yloxypropynyl)-estra-3,5-dien-173-01 (18 g. is dissolved in 750 ml. of methanol at room temperature. Thereafter, 20 g. of oxalic acid is dispersed in 150 ml.

of water and the resultant aqueous oxalic acid solution is added to the steroid methanol solution at room temperature in a portionwise fashion. The resulting reaction mixture is left overnight at room temperature. The reaction mixture is then neutralized by the portionwise addition of sodium hydroxide and the neutralized mixture is filtered. The filtrate is concentrated in vacuum to a residue. The residue is extracted with an ether:- mcthylene chloride mixture to provide a solution which is then dried over sodium sulfate. The dried solution is evaporated to obtain a solid. The solid is chromatographed on a column of silica gel eluting with hexanezethyl acetate to obtain a substance which is recrystallized from ethyl acetatezhexane to obtain the l7a-(3- hydroxypropynyl )-estr-4-enl 7B-ol-3-one product. l7a-( 3-Tetrahydropyran-2'-yl0xypropynyl)- 1 7B- acetoxy-estr-4-en-3-one 18 g. is dissolved in 750 ml. of methanol at room temperature. Thereafter, 20 g. of oxalic acid is dispersed in 150 ml. of water and the resultant aqueous oxalic acid solution is added to the steroid methanol solution at room temperature in a portionwise fashion. The resulting reaction mixture is left overnight at room temperature. The reaction mixture is then neutralized by the portionwise addition of sodium hydroxide and then the neutralized mixture is filtered. The filtrate is concentrated in vacuum to a residue. The residue is extracted with an etherzmethylene chloride mixture to provide a solution which is then dried over sodium sulfate. The dried solution is evaporated to obtain a solid. The solid is chromatographed on a column of silica gel eluting with hexanezethyl acetate l: l) to obtain a substance which is recrystallized from ethyl acetate: hexane to obtain the 170143- hydroxypropynyl l 7,8-acetoxy-estr-4-en-3-one product & a crystalline solid.

Preparation 3 A mixture of 20 ml. of absolute pyridine, 8 ml. of freshly distilled thionyl chloride, and ml. of absolute tetrahydrofuran is prepared at room temperature with stirring. l7a-( 3-Hydroxypropynyl )-estr-4-enl 7B-ol- 3-one (3.4 g.) which is dissolved in 50 ml. of anhydrous tetrahydrofuran are added to the resulting solution over a 25 minute period at room temperature. After the addition is complete, the reaction mixture is stirred at room temperature for 35 minutes. After this period of time, the mixture is poured into ice water and the resulting mixture is extracted with etherzmethylene chloride. The extracts are washed with water and dried over sodium sulfate. The dried material is evaporated to an oil. The oil is chromatographed on silica gel to obtain the desired l7a-(3-chloropropynyl)-estr-4-en-17,8-01- 3-one product.

A mixture of 20 ml. of absolute pyridine, 8 ml. of freshly distilled thionyl chloride, and 90 ml. of absolute tetrahydrofuran is prepared at room temperature with stirring. l7a-( 3-Hydroxypropynyl l 7B-acetoxyestr-4- en-3-one (3.4 g.) which is dissolved in 50 ml. of anhydrous tetrahydrofuran is added to the resulting solution over a 25 minute period at room temperature. After the addition is complete, the reaction mixture is stirred at room temperature for 35 minutes. After this period of time, the mixture is poured into ice water and the resulting mixture is extracted with etherzmethylene chloride. The extracts are washed with water and dried over sodium sulfate. The dried material is evaporated to an oil. The oil is chromatographed on silica gel to obtain the desired 17a1-( 3-chloropropynyl l 7B-acetoxyestn 4-en-3-one product.

In like manner, the foregoing procedures can be practiced on the corresponding l8-alkyl compounds thus providing as final compounds, 1701-(3- chloropropynyl l 8-methylestr-4-enl 7,8-ol3-one, l7- a-(3-chloropropynyl)18-ethylestr 4-cn-17B-ol-3-one, 17a-(3-chloropropynyl)-18-n-propylestr-4-en-17B-ol- 3-one.

Preparation 4 To a slurry of l.() g. of sodium hydride in 10 ml. of dry diethyleneglycol dimethyl ether under a dry nitrogen atmosphere is slowly added 1.0 g. of 3-methoxyl70z-ethynylcStra-1,3,5(10) -trien-l7B-ol in 10 ml. of dry diethylcneglycol dimethyl ether in a dropwise fashion over minute period. To this mixture is added dropwise, 0.9 g. of 2-chlorotetrahydropyran over a 10 minute period.

The mixture is stirred at room temperature for an additional 30 minutes and then cautiously added to an ice water mixture with stirring. The organic phase is extracted with diethyl ether, dried and evaporated under reduced pressure to yield 3-methoxy-l7a-ethynyl-17B- tetrahydropyran-2'-yloxyestral ,3 ,5( 1O )-triene which may be further purified via recrystallization from acetonczhexane.

A solution of 2.5 grams of phenyllithium in ml. of diethyl ether is prepared. While maintaining this solu tion at room temperature, 10 grams of 3-methoxy-17oz ethynyl-17B-tetrahydropyran-2-yloxyestra-l,3,5( 1O triene are added thereto to provide a solution containing 3-methoxy-17a-ethynyl1ithium-17B- tetrahydropyran-2-yloxyestra1,3,5( lO)-triene. To the resulting solution is added, portionwise and with stirring, 4 grams of par-aformaldehyde. The addition is conducted at a rate to maintain gentle reflux of the solution. After the addition, the mixture is stirred for 20 hours, and then poured into water and extracted with ether. The ether extracts are washed with water, dried and evaporated to obtain the 3-methoxy-l7oz-(3- hydroxypropynyl)-17,8-tetrahydropyran-2-yloxyestra- 1,3,5( l0)-triene product.

3-Methoxy-l7a-( 3-hydroxypropynyl)-17B tetrahydropyran-Z-yloxyestra-1,3,5(10)-triene (l g.) is dispersed in 50 ml. of anhydrous ether at room temperature with stirring. To the resultant solution is added 1.5 ml. of purified thionyl chloride. The addition is conducted portionwise at 0C. The resulting reaction mixture is then allowed to stand at 0C. for a period of 6 minutes after which time it is washed with aqueous sodium bicarbonate solution followed by water. The washed material is then dried over sodium sulfate and evaporated to dryness to obtain the 3-rnethoxy- 1 701-( 3- chloropropyny1)-17B-tetrahydropyran-2'-yloxyestral,3,5(10)-triene product which is recrystallized from ether-ethyl acetate.

Alternatively, the 17a-( 3-chloropropynyl) pound is prepared as described in Preparation 5.

To a solution of 1 g. of 3-methoxy-17a-(3- chloropropynyl)-17f3-tetrahydropyran-2yloxyestra- 1,3,5( 10) -triene in ml. of dioxane is added 0.5 ml. of 2 N hydrochloric acid. The mixture is allowed to stand 5 hours at room temperature and then diluted with ice water and extracted with methylene Chloride. The extracts are washed with water to neutrality dried over sodium sulfate, and evaporated to dryness to yield com 3-methoxy-17ot-(3-chloropropynyl estra-1,3 ,5( 1(1) -trien-l7B-ol which is recrystallized from acetonezhexane.

Preparation 5 Alternative to the procedures described in Preparations 3 and 4 the following can be employed to prepare the 3-chloropropynyl compounds:

A solution of 17a-(3-hydroxypropynyl)-17,8-acetoxyestr-4-en-3-one (3.5 g.) and triphenylphosphine (4.2 g.) in dimethylformamide (26.7 ml.) containing carbon tetrachloride (1.1 ml.) is heated at 1 10for 15 minutes and then the solvent is evaporated under reduced pressure. The residue is dissolved in hexane-ether (3:1 and chromatographed on 140 g. of silica gel. Elution with etherhexane (2:1) and crystallization of the pooled crystalline fractions from hexane furnishes l7a-(3- chloropropynyl)-17,8-acetoxyestr-4-en-3-one.

In accordance with the above procedure, 17a-(3- chloropropynyl)estr-4-en-17B-ol-3-one is prepared from 170z-(3hydroxypropynyl)-estr-4-en-173-01- 3-one.

Similarly, 17a-( 3-ch1oropropynyl l 7B-acetoxyestrl8-methylestr-4-en-3-one, 6,6-difluoro- 1 7a-( 3- chloropropynyl)-17B-acetoxyestr-4-en-3-one, and 6,6- difluoro-l7oz-(3-chloropropynyl)-17B-acetoxy-l 8- methylestr-4-en-3-one are prepared. Base hydrolysis thereof affords the corresponding 17B-ols, or the chlorination can be performed on the 178-01.

Preparation 6 l7oc-( 3-Hydroxypropynyl )-estr-4-enl 7fi-ol-3-one 1.5 g.) is dissolved in ml. of toluene. The resulting solution is mixed with 2 g. of benzene sulfonyl fluoride. The reaction mixture is then heated to a temperature ranging from to C. and for a period of 4 hours. At the end of this reaction period, the mixture is cooled and then poured into ice water. The organic layer is then washed with a sodium bicarbonate solution and then with water and, following the washings, is dried over sodium sulfate. Solvent is then removed by evaporation and the remaining residue is recrystallized from ether to obtain the 17a-(3-fluoropropynyl)-estr-4-enl7B-ol-3-one product.

Alternatively, the 3-fluoropropynyl compounds, prepared as described above, are prepared by the following representative procedure:

A solution of l g. of l7a-(3-hydroxypropynyl)-17fiacetoxyestr-4-en-3-one in ml. of anhydrous methylene dichloride and 1 g. of l-diethylamino-l,1,2-trifluoro-Z-chloroethane is allowed to stand at room temperature for 48 hours. The reaction mixture is then filtered through alumina, eluting with hexane, to give 17- a-(3-fluoropropynyl)-17,8-acetoxyestr-4-en-3-one which can be recrystallized from acetonethexane.

Alternatively, the above method is practiced in acetonitrile at room temperature for about 24 hours or with tetrahydrofuran at reflux for about 1 hour.

Preparation 7 A solution of 3-tetrahydropyran-2-yloxyprop-l-yne (12.0 g.) in dry tetrahydrofuran (100 m1.) is added to a solution of ethylmagnesium bromide prepared from ethyl bromide (8.2 g.) and magnesium turnings 1.8 g.) in tetrahydrofuran (151) ml.). The reaction mixture is heated under reflux for 5 minutes and after being allowed to stand at room temperature for 2 hours it is treated with a solution of 3-ethoxyestra-3,5-dicnl7'one 10.0 g.) dissolved in dry tetrahydrofuran 150 ml.). After 2 hours, the reaction mixture is poured into saturated ammonium chloride solution and the 3- ethoxyl 704-( 3-tetrahydropyran-2-yloxypropynyl estra-3,5-dien-l7B-ol product is isolated by extraction with methylene dichloride.

A solution of 3-tetrahydropyran-2'-yloxyprop-l-yne (7.1 g.) in dry tetrahydrofuran (50 ml.) is added to a solution of ethylmagnesium bromide prepared from ethyl bromide (4.0 g.) and magnesium turnings (0.9 g.) in tetrahydrofuran (75 ml.). The reaction mixture is heated under refulx for 5 minutes and after being allowed to stand at room temperature for 30 minutes it is treated with a solution of 3ethoxyestra-3,5-dien- 17-one (5.0 g.) in dry tetrahydrofuran (65 ml.). After 8 hours, acetyl chloride (20 ml.) is added and the reaction mixture is kept at room temperature for l8 hours and then poured into water. The crude product, isolated by extraction with methylene dichloride, is dissolved in methanol ml.) containing 0.25 ml of concentrated hydrochloric acid and the resulting solution heated under reflux for 10 minutes. Addition of water (200 ml.) and isolation by extraction with methylene dichloride furnishes a crystalline solid which is purified by chromatography over Florisil (200 g.) Elution with ethyl acetate-hexane 1:4) gives 1704-(3- hydroxypropynyl l 7B-acetoxyestr-4-en-3-one after crystalline from ether.

The thus prepared compound is treated in accordance with the chlorination procedures of Preparation 3 or Preparation 5 to give l7a-(3-chloropropynyl)- 17B-acetoxy-estr-4-en-3-one. In a similar manner, but with elimination of the acetyl chloride treatment step, l7a( 3-chloropropynyl)-estr-4-enl7B-ol-3-one is prepared.

ln accordance with the above procedures, l7a-(3- chloropropynyl)-17,8-acetoxy-l8-methylestr-4-en- 3-one, l70z-( 3-chloropropynyl l 8-methylester-4-en- I 7B-ol-3-one, 6,6-difluorol 7o 3-chloropropyny] l7,8acetoxyestr-4-en-3-one, 6,6difluoro 1 7a-( 3- chloropropynyl)-4-enl 7,8-ol-3-one, 6,6-difluoro- 1 7a- (3-chloropr0pynyl)-l7,8-acetoxy-18-methylestr-4-en- 3-one, 6,6-difluoro-l7a-(3-chloropropynyl)-18- methylestr-4-en-l7B-ol-3-one are prepared from the respective starting compounds. The 1713-01 compounds can also be prepared upon final base hydrolysis of the l7B-acetate products.

Preparation 8 l7a( 3-Bromopropynyl )-androst-4-enl 7,B-ol-3-one is prepared by substituting thionyl bromide for thionyl chloride in Preparation 3 and by substituting carbon tetrabromide for carbon tetrachloride in Preparation 5. This can be acetylated to the l7B-acetate. Likewise, by employing the appropriate starting compounds, the corresponding l8-methyl, -ethyl, and -propyl derivatives are prepared. Similarly, these procedures are applicable in the preparation of the 1711- (bromopropynyl) derivatives in the estrogen and estrane series.

Preparation 9 A mixture of l g. of l70z-(3-hydroxypropynyl)-l7/5 acetoxyestr-4-en-3-one in 5 ml. of pyridine and 0.5 g. of methanesulfonyl chloride is allowed to stand at room temperature for 24 hours and is then diluted with water and filtered. The solid thus collected is dried and recrystallized from acetoneihexane to yield l7a-(3- methylsulfonyloxypropynyl l 7B-acetoxyestr-4-en- 3-one.

Similarly, l7a-(3-p-tolylsulfonyloxypropynyl)-17B- acetoxyestr-4-en-3-one is prepared by substituting ptoluenesulfonyl chloride for methanesulfonyl chloride in the foregoing-procedure. Likewise, the corresponding l7a(3-methylsulfonyloxypropynyl) and 17a-(3-ptolylsulfonyloxypropynyl) derivatives of the other l7a-(3-hydroxypropynyl) starting compounds of the present invention are prepared.

Also prepared are the corresponding l7B-(3-ethanesulfonyloxypropynyl), -(3-propanesulfonyloxypropynyl 3-benzenesulfonyloxy and 3- mesitylenesulfonyloxy) derivatives.

Preparation 1 0 A stream of perchloryl fluoride is passed through a solution of l g. of 3-ethoxyestra3,5-dien-170ne in 25 ml. of dimethylformamide. cooled to 0C., for 5 minutes. After being allowed to slowly attain a temperature of 20C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed with saturated aqueous sodium bicarbonate solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue is then chromatographed on alumina to yield a mixture of the 6afluoro and ofi-fluoro isomers. To the mixture in 7.5 ml.

of anhydrous, peroxide-free dioxane is added 1.2 ml. of

freshly distilled ethyl orthoformate and 0.8 g. of p-tol uenesulfonic acid. The mixture is stirred at room temperature for 15 minutes and allowed to stand at room temperature for 30 minutes. There is then added 0.8 ml. of pyridine, followed by water until solidification occurs. This solid is collected by filtration, washed with water and air dried to yield 3-ethoxy- 6-fluoroestra-3,5- dien-l7-one which is recrystallized from acetonezhexane.

A stream of perchloryl fluoride is passed through a solution of l g. of 3-ethoxy-6-fluoroestra'3,S-dien- 17-one in 25 ml. of dimethylformamide, cooled to 0C., for 5 minutes. After being allowed to slowly attain a temperature of 20C., the solution is poured into water and extracted with ethyl acetate. These extracts are washed with saturated aqueous sodium bicarbonate solution and with water to neutrality, dried over sodium sulfate and evaporated to dryness. The residue is then chromatographed on alumina to provide 6,6-difluoroestr -4-ene-3, l 7-dione product on recrystallization from acetone:hexane.

In like manner, 6,6-difluoroandrost-4-ene-3,17- dione, 6,6-difluoro-l8-methylestr-4-ene-3,17-dione, 6,6-difluoro-.l 8-methylandrost-4-ene-3, l 7-dione, 6,6- difluoro-l 8-ethylestr4-ene-3, l 7-dione, 6,6-difluoro- 18-ethylandrost-4-ene- 3 l 7-dione, 6,6-difluorol 8- propylestr-4-ene-3, l 7-dione, and 6,6-difluoro-18- propylandrost-4-ene-3, l 7-dione are prepared from the respective starting compound.

Preparation 1 l A mixture of l g. of 17 B-acetoxyestr-4-en-3-one, 25 ml. of dry benzene, 5 ml. of ethylene glycol, and 50 mg. of p-toluenesulfonic acid monohydrate is refluxed for 16 hours using a water separator. The reaction mixture is then washed with aqueous sodium bicarbonate solution and water, dried and evaporated to dryness. The

resultant residue is chromatographed on alumina eluting with hexane:benzene and pure benzene to yield 3,3- ethylenedioxy-l7/3-acetoxyestr-5( l)-ene-which is recrystallized from acetonezhexane.

To a solution of 1.0 g. of 3,3-ethylenedioxy-l7B- acetoxyestr-( l())-ene in 50 ml. of benzene is added (1.2 g. of magnesium sulfate. The mixture is heated at reflux for 40 minutes, neutralized with a saturated aqueous sodium carbonate solution, concentrated under reduced pressure to about 20 ml. and poured into water. The solid which forms is collected by filtration, washed well with water, and dried to yield l7aacetoxyestr-5( l())-en-3-one which may be recrystallized from acetone.

One gram of 3,3-ethylenedioxy-17B-acetoxyestr- 5( l0)-ene is disposed in 45 ml. of acetone containing 0.05 mg. of malonic acid in 5 ml. of water and the resultant mixture is allowed to stand at room temperature overnight. After this time it is poured into dilute aqueous potassium bicarbonate solution and extracted with ether. The extracts are dried and evaporated to give 17- B-acetoxyestr-5( l())-en-3-one.

To a solution of 0.2 g. of l7B-acetoxyestr-5( l0)en 3-one in 4 ml. of pyridine is added 1.1 g. of pyridine perbromide hydrobromide. The mixture is stirred at room temperature for 7 hours after which time it is partitioned between water and ethyl acetate and the organic phase separated. This is washed successively with dilute hydrochloric acid, dilute sodium bicarbonate solution. dried and evaporated. The resultant solid is chromatographed on alumina eluting with benZeneIether and pure benzene to give l7B-acetoxyestra- 4,9( l0)-dien-3-one.

A solution of l g. of l7/3-acetoxyestra-4,9( l0)-dien- 3-one in 50 ml. of methanol is heated at reflux for 3 hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms collected by filtration. washed with water to neutrality and dried to yield estra- 4,9( lO)-dienl7B-ol-3-one which is recrystallized from methylene chloridezether.

A solution of 6 g. of estra-4,9( l0)-dien-17B-ol-3-one in 120 ml. of pyridine is added to a mixture of 6 g. of chromic trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate, and filtered through water, dried and evaporated to dryness to yield extra- 4,9()-diene-3,l7-dione which may be further purifled by recrystallization from acetonezhexane.

Likewise, l8-methylestra-4,9( 10)-diene-3, l 7-dione, l8ethylestra-4,9( l0)-diene-3,20-dione, and l8- propylestra-4,9( 10)-diene-3,17-dione are prepared.

Estra-4,9(10)-dien-l7B-ol-3-one (2 g.) is added to a solution of hydrogen chloride l .g.) in methanol (100 ml.). After minutes at room temperature, the solution is cooled in ice and is neutralized with powdered sodium methoxide. Methylene chloride (300 ml.) is then added and the mixture is washed several times with water. The dried solvent is evaporated and the residual gum is exhaustively extracted with boiling nhexane. The extract is chromatographed on Florisil (50 g.). The column is eluted with 1%, 2%, 3%, and 4% acetone in petroleum ether (b.p. 60). The gum eluted in the latter is dissolved in acetone ml.) and the solution is treated with sulfuric acid (0.5 ml.; 8%). After 5 minutes, the mixture is diluted with water and the crystals which separate are collected, washed with water. and dried. Recrystallization from n-hexane gives the estra-5( lO),9( l l )-dien-l7B-ol-3-one.

A solution of 6 g. of estra-5(10),9( l l )-dien-l7B-ol- 3one in 120 ml. of pyridine is added to a mixture of 6 g. of chromic trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield estra-5( lO),9( l l )-diene-3, l 7-dione which may be further purified by recrystallization from acetonezhexane.

Likewise l8-methylestra-5( lO),9( 1 l )-diene-3,l 7- dione, 18-ethylestra-5( lO),9( l l )-diene-3, l 7-dione, and l8-propylestra-5( lO),9( l l)-diene-3,l7dione are prepared.

A mixture of 2.0 g. of estra4,9( l0)-diene-3.l7- dione, 100 ml. of dry benzene, 10 ml. of ethylene glycol and 250 mg. of p-toluenesulfonic acid monohydrate is refluxed under nitrogen for 6 hours. The reaction mixture is then washed with benzene, aqueous sodium bicarbonate solution, and water, dried and evaporated to dryness to yield 3,3;17,l7-bisethylenedioxyestra- 5( lO),9( l l )-diene which is recrystallized from acetonezhexane.

The above procedure is repeated using estra-4,9( l0 dien-l 7,8ol3-one to give 3,3-ethylenedioxyestra- 5( lO),9( l l )-dienl7B-ol-3-one which is oxidized with Collins reagent as described above to give 3,3- ethylenedioxyestra-5( lO),9( l l )-dien-l7-one.

To a solution of 1.75 g. of 3,3;l7,l7-bisethylenedioxyestra-5( lO),9( l l )-diene in 5 ml. of methylene chloride is added 1.2 g. of m-chloroperbenzoic acid. The reaction mixture is kept at room temperature for 20 minutes. The mixture is then extracted with methylene chloride, the extracts washed with dilute sodium bicarbonate solution and water, and evaporated to yield an oil.

The oil thus obtained is chromatographed on silica with 1:1 ethyl acetatezhexane and treated at 25C. with 0.05 ml. of perchloric acid for 20 minutes. Isolation via chromatography yields estra-4,9( 10),l ltriene-3,17-dione.

Similar results are obtained when perbenzoic acid is substituted for m-chloroperbenzoic acid in the epoxidation procedure. In like manner, sulfuric acid or other strong acid can be substituted in lieu of perchloric acid in the last procedure with successful results.

The oil obtained upon epoxidation as described above is alternately dissolved in 100 mg. of p-toluenesulfonic acid. The mixture is kept at room temperature for 20 hours and is then evaporated to an oily mixture containing the corresponding hydroxy derivatives. These latter derivatives may be isolated via chromatography or the oil may be treated with perchloric acid or other mineral acid as described above to similarly yield estra-4,9( l0),l l-triene-3, l7-dione.

Likewise prepared by the procedures of this example is l8-methylestra-4,9( 10),1 l'triene-3,l7-dione.

A solution of 2 g. estra-4,9( 10),l l-triene-3,l7-dione in 20 ml. of anhydrous tetrahydrofuran is cooled to C. in a dry ice-acetone bath and treated with a previously cooled solution of 0.6 g. of lithium tri-t-butoxy aluminum hydride in 20 ml. of anhydrous tetrahydrofuran. After maintaining the reaction mixture at reflux for 15 minutes it is cooled and poured into ice water and extracted several times with ethyl acetate. These extracts are Washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness to yield estra-4,9( 10),1 l-triene-3B, l 7B-diol.

A mixture of l g. of estra-4,9( l),l l-triene-3,B,l7B- diol, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3B-acetoxyestra-4,9( l()).l ltrien-l7B-ol which is recovered by chromatography on silica gel.

A solution of 6 g. of 3B-acetoxyestra-4,9( ),l ltrien- 1 73-01 in 120 ml. of pyridine is added to a mixture of 6 got chromic trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield 3B-acetoxyestra-4,9(10),] l-trien-l7-one which may be further purified by recrystallization from acetonezhexane.

Also thus prepared are 3,8-acetoxy-l8-methylestra- 4,9-( l0),l l-trienl 7-one and 3,8-acetoxyl 8- ethylestra-4,9( lO),l l-trien-l7-one and 3,8-acetoxy-18- propylestra-4,9( l0),l l-trien-l7-one.

Preparation 12 A mixture of l g. of estra-4,9( lO)-diene-3,l7-dione, 7.5 ml. of dry benzene, 5 ml. of ethylene glycol and 2 g. of oxalic acid dihydrate is refluxed for 16 hours using a water separator. The reaction mixture is then washed with aqueous sodium bicarbonate solution and water, dried and evaporated to dryness to yield 3,3- ethylenedioxyestra-4,9( l0)-dien-17-one which is recrystallized from acetonezhexane.

Alternatively, the above procedure can be employed using estra-4,9( l0)-dien-l7B-ol3-one to give the 3,3- ethylene ketal followed by oxidation with Collins reagent to give 3,3-ethylenedioxyestra-4,9( l0 )-dienl7-one.

Likewise, 3 ,3-ethylenedioxyl 8-methylestra- 4,9( 1 0)-dien-1 7-one, 3,3-ethylenedioxyl S-ethylestra- 4,9( l0)-dienl 7-one, 3,3-ethylenedioxyl 8-propylestra4,9( l0 )-dienl 7-one, 3,3-ethylenedioxyestra- 5( l0),9( l l )-dienl 7-one, 3,3-ethylenedioxy-l8- methylestra-5( l0),9( l l )-dien-l7-one, 3,3- ethylenedioxyl 8-ethylestra-5( l0),9( l l )-dienl 7-one, 3,3-ethylenedioxyl 8-propylestra-5( l0),9( l l )-dien- 17-one, 3,3-ethylenedioxyestra-4,9( lO),l l-trienl7-one, 3,3-ethylenedioxy-l 8-methylestra-4,9( l0),l ltrienl 7-one, and 3,3-ethylenedioxy-1 8-ethylestra- 4,9(10),1 l-trien-l7-one are prepared from the respective starting compounds.

One gram of estra-4,9(10)-diene-3,l7-dione is suspended in 10 ml. of anhydrous methanol containing 0.16 ml. of perchloric acid (70%) per liter of methanol. The reaction mixture is stirred at room temperature and under anhydrous conditions overnight. Solid sodium methoxide is then added and the reaction mixture is then slowly diluted with from 5 to 10 times its volume with water. The mixture is then filtered to give 3,3- dimethoxyestra-4,9( lO)-dien-17-one.

Likewise, the 3,3-dimethoxy compounds otherwise corresponding to those listed in paragraph three hereof are prepared.

The compounds prepared as described in Preparations 1 l and 12 are treated in accordance with the procedures of Preparations 1 to 9 to give:

l7oz-( 3-tetrahydrofuran-2-yloxypropynyl )estra- 17a-( 3-tetrahydrofuran-2-yloxypropynyl )estra- 4,9( 10 )-dienl 7,8-ol-3-one,

17a-( 3-tetrahydrofuran-2 '-yloxypropynyl )estra- 5( l0),9( l 1 )-dien-17B-o1-3-one,

17oz-(3-tetrahydropyran-2'-yloxypropynyl)estra- 4,9( 1()),l l-trienl 7B-ol-3-one,

l7a-( 3-tetrahydropyran-2-yloxypropynyl )estra- 4,9( lO)-dien-17Bol-3-one,

17a-( 3-tetrahydropyran-2'-yloxypropynyl )estra- 5(10),9(1l)-dien-17,B-ol-3-one,

1 7a-( 3-( 4-methoxytetrahydrofuran-4-yloxy )propynyl) estra4,9( l0),1 l-trien-l7B-ol-3-one,

1 7a-( 3-( 4-methoxytetrahydrofuran-4'-yloxy)propynyl) estra-4,9( 10)-dien-17B-ol-3-one,

l7oz 3-( 4-methoxytetrahydrofuran-4 '-ylo xy )propynyl) estra-5(10),9(l l )-dien-l7B-ol-3-one,

l7a-( 3-tetrahydrofuran-2'-yloxypropynyl )-l 8- methylestra-4,9( lO),1 l'trienl 7B-ol-3-one,

170z-( 3-tetrahydrofuran-2'-yloxypropynyl )-l 8- methyl-estra-4,9( 10 )-dienl 7,8-o'l-3-one,

l7a-( 3-tetrahydrofuran-2-yloxypropynyl l 8- methylestra-5( l0),9( l l )-dien-l7,8-ol-3-one,

l7oz-tetrahydropyran-2 -yloxypropynyl l 8- methylestra-4,9( lO),l l-trienl 7,8-ol-3-one,

l7a-tetrahydropyran-2'yloxypropynyl l 8- methylestra-4,9( l0 )-dienl 7B-ol-3-one,

l7a-tetrahydropyran-2'-yloxypropynyl )-l 8- methylestra-5( 10)9( l l )-dien-17B-ol-3-one,

l7a-( 3'( 4-methoxytetrahydropyran-4'- yloxy )propynyl l 8-methylestra-4,9( 10) ,1 l-trien-17B- ol-3-one,

17a-( 3-(4-methoxytetrahydropyran-4'- yloxy )propynyl)- l 8-methylestra-4,9( l0)-dien-17B-ol- 3-one,

l7a-( 3-( 4'methoxytetrahydropyran-4'- yloxy)propynyl l 8-methylestra-5( 10)9( 1 1 )-dienl7B-ol-3-one,

17a-( 3-tetrahydrofuran-2-yloxypropynyl l 8- ethylestra-4,9( lO),1 l-trienl 7,B-ol-3 -one,

l7a-( 3-tetrahydrofuran-2 -yloxypropynyl l 8- ethylestra-4,9( l0 )-dienl7B-ol-3-one,

l7a-( 3-tetrahydrofuran-2 -yloxypropynyl l 8- ethylestra-5( 10)9( l l )dien-l7B-ol-3-one,

17a-(3-tetrahydropyran-2'-yloxypropynyl)-l8- ethy1estra-4,9( 10),] 1-trien-l7B-ol-3-one,

l7a-( 3-tetrahydropyran-2 '-yloxypropynyl l 8- ethylestra-4,9( lO)-dienl 7B-ol-3-one,

l7oz-( 3-tetrahydropyran-2 '-yloxypropynyl l 8- ethylestra-5( l0 )9( l 1 )-dienl7B-ol-3-one,

l7a-( 3-( 4-methoxytetrahydropyran-4 yloxy )propynyl l 8-ethylestra-4,9( l0 ,1 l-trie'n- 1 7B- ol-3-one,

l7B-( 3-( 4-methoxytetrahydropyran-4'- yloxy)propynyl)-1 8-ethylestra-4,9( 10)-dienl 7,B-ol- 3-one,

1 7a-( 3-( 4O -methoxytetrahydropyran-4 yloxy )propynyl l 8-ethylestra-5( l0 )9( l l )-clien- 1 7B- ol-3-one,

l7a-( 3-tetrahydrofuran-2 -yloxypropynyl)- l 8- propylestra-4,9( 10), l l-trienl 7 B-ol-B-one,

1 7a-( 3-tetrahydrofuran-2 '-yloxypropynyl )-l 8- propylestra-4,9( 10)-dienl 7B-ol-3-one,

17 a-( 3-tetrahydrofuran-2'-yloxypropynyl l 8- propylestra-S( l())9( l l )-dienl 7B-ol-3-one.

l 7a-( 3-tetrahydropyran-2-yloxypropynyl )-l 8- propylestra-4,9( 10),] l-trien-l 7,8-ol-3-one.

l7a-( 3tetrahydropyran-2'-yloxypropynyl )-l 8- propylestra-4,9( l )-dienl 7B-ol-3-one,

l7a-( 3-( 4'-methoxytetrahydropyran-4- yloxy)propynyl)-l8-propylestra-4,9( l()),l l-trien-l7/3- ol-3-one,

l7a-( 3-( 4'-methoxytetra.hydropyran-4- yloxy )propynyl l 8-propylestra-4,9( l0 )-dien- 1 78-0]- 3-one,

l 704-( 3-( 4-methoxytetrahydropyran-4'- yloxy )propynyl 8-propylestra-5( l() )9( l )-dien- 1 7B- ol-3-one.

l7a-( B-halopropynyl )estra-4,9( l()),] l-trienl 7,8-01- B-one,

l7a-( B-halopropynyl )-estra4,9( lO)-dien- 1 75-0]- 3-One,

l7a-( 3-halopropynyl)estra-5( l0)9( l l )-dien-l7,8-ol- 3-onc,

l7u-( 3-halopropynyl l 8-methylestra-4,9( l0), l-tricn-l 7B-ol-3-one,

l7a-( 3-halopropynyl )-l 8-methylestra-4,9( lO)-dienl7B-ol-3one.

l70z-( 3-halopropynyl l 8-methylestra-5( l0)9( l l dienl 7,8-ol-3-one,

l 7a-( 3-methylsulfonyloxypropynyl )estra- 4,9( l()),] l-trien-l7B-ol-3-one,

l7a-( 3-methylsulfonyloxypropynyl )estra-4,9( l0)- dicn-l7B-ol-3-one,

l7a-( 3-methylsulfonyloxypropynyl )estrall))9( l l )-dicn-l7B-ol-3one,

l70z-( 3-methylsulfonyloxypropynyl l 8-methylestra- 4,9(l0),1l-trien-l7B-ol-3-one.

l'7a-( 3-methylsulfonyloxypropynyl )-l 8-methylestra- 4,9( lO)-dien-l7,8ol-3-one,

l7a-( 3-methylsulfonyloxypropynyl 8-methylestra- 5( l0)9( l l )-dien-l7,8-ol-3-one,

l7a-p-tolylsulfonyloxypropynyl )estra-4.9( 10), l l-trienl 7Bol-3-one,

l7a-p-tolylsulfonyloxypropynyl )-estra-4,9( 1O )-dienl7B-ol-3-one,

l7a-p-tolylsulfonyloxypropynyl )-estra-5( lO),9( l l dienl 7,B-ol-3-one,

l 7a-p-tolylsulfonyloxypropynyl )-l S-methylestra- 4,9-(10), l l-trienl7B-ol-3-one,

l7a-p-t0ylsulfonyloxypropynyD-1S-methylestra- 4,9( l0)-dien-l7B-ol-3-one,

l7oz-p-tolylsulfonyloxypropynyl l S-methylestra- 5( l0), 9( l l-dienl7,8-ol-3-one and so forth.

The foregoing l7B-hydroxy compounds can be esterified under conventional tertiary carbinol conditions to give the corresponding l7B-acetates thereof.

Preparation 13 A solution of l g. of sodium borohydride in 3 ml. of water is added to an ice-cooled solution of l g. of 6,6- difluoroestr-4-ene-3,l7-dione in 120 ml. of methanol and the mixture is allowed to stand for 16 hours at room temperature. The excess reagent is decomposed by the addition of acetic acid and the solution is then concentrated to a small volume in vacuo and diluted with water. The product is extracted with ethyl acetate and these extracts are washed with water, dried and evaporated to yield 6.6-difluoroestr-4-ene-3B,l7,8-diol which may be further purified by recrystallization from acetonezhexane.

A mixture of 3 g. of 6,6-difluoroestr-4-ene-3B,17,8- diol. 10 ml. of pyridine and 0.9 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3B,17B-diacetoxy-6,6- difluoroestrl-ene, 3B-acetoxy-6,6-difluoroestr-4-en- 178-0] and 6,6-difluoro l 7B-acetoxy-estr-4-en-3B-ol which are separated by chromatography.

A solution of 6 g. of 3B-acetoxy-6,6diflu0roestr-4- en-l7/3-ol in 120 ml. of pyridine is added to a mixture of6 g. of chromic trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield 3,8-acetoxy-6,6-diflu0roestr-4-en-]7-one which may be further purified by recrystallization from acetone:hexane.

In like manner, 3,Bacetoxy-6,6-difluorol 8- methylestr-4-en-l7-one is prepared from 6.6-difluorol8methylestr-4-ene-3, l 7-dione.

The thus prepared derivative is treated in accordance with the procedures set forth above to prepare the 3,8- acetoxy-6,6-difluoro- 1 7a-( 3-tetrahydropyran-2 yloxypropynyl)-estr-4-en-17,8-0] which is converted to the corresponding l7a-(3-hydroxypropynyl), 17a-(3- halopropynyl l7a-( 3-methylsulfonyloxypropynyl) and l7a-3p-toluenesulfonyloxypropyny]) derivatives via the procedures set forth above. Also thus prepared is 3,8,] 7,8-diacetoxy-6,o-difluoro-l 701-(3- halopropynyl) androst-4-ene and 3,8,17,8-diacetoxy- 6,6-difluorol 704-( 3-methylsulfonyloxypropynyl androst-4-ene and 3,8, 7B-diacetoxy-6,6-difluoro-l 7a- (3-p-tolylsulfonyloxypropynyl)-androst-4-ene and 3B,- ]7,8-diacetoxy-6,o-difluoro- 1 7a-( 3-tetrahydrofuran- 2'-yloxypropynyl )-androst-4-ene and 3 [3,17B- diacetoxy-6,6-difluoro- 1 7a-( 3-(4- methoxytetrahydropyran-4'-yloxypropynyl.

Likewise prepared are the 3,8-acetoxy-l7a-(3- substituted propynyl)-estra-4,9-( 10),] ltriene compounds wherein the substituent is tetrahydrofuran-2- yloxy, tetrahydropyran-2-yloxy, 4-methoxytetrahydropyran-4-yloxy, halo, methylsulfonyloxy, and ptolylsulfonyloxy.

Substitution of an alternate carboxylic acid anhydride in the above procedures affords the corresponding acylates, for example, the propionates, benzoates, pentanoates, and adamanatoates, for example.

3B-propionyloxy-6,6-diflu0rol z-( 3-halopropynyl l 9-norandrost-4-enl 7 B-ol,

3 B-propionyloxy- 1 7a-( 3-halopropynyl )estra- 3/3-acetoxy-6,6-difluoro- 1 7a-( B-methylsulfonyloxypropynyl )-l 8-ethylestr-4-en- 1 78-0],

3,8-propionyloxy-6,6-difluoro- 7a-( 3-ptolylsulfonyloxypropynyl )-androst-4-en- 1 78-0],

BB-benzoyloxy- 1 7a( 3-tetrahydropyran-2- yloxypropynyl )-estra-4,9-( l0 ),1 1-trien-l 78-01,

3B-benzoyloxy- 70z-( 3- benzenesulfonyloxypropynyl l 8-methylandrost-4-enl7B-o],

3 B-benzoyloxy- 1 7a-( 3-benzenesulfonyloxypropynyl- 18-methylestra-4,9( 10),] l-trien-l7B-ol. and

3 Badamantoyloxy- 1 7a-( 3-halopropynyl l 8- methylestr--( l0)-en-l7,8-ol, and so forth.

Preparation 14 A solution of 2 g. of o 6-difluoroestr-4-enc-3 l7- dione in 20 ml. of anhydrous tetrahydrofuran is cooled to 31 75C. in a dry ice-acetone bath and treated with a previously cooled solution of 0.6 g. of lithium tri-tbutoxy aluminum hydride in 20 ml. of anhydrous tetrahydrofuran. After maintaining the reaction mixture at reflux for 15 minutes it is cooled and poured into ice water and extracted several times with ethyl acetate. These extracts are washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness to yield 6,6-difluoroestr-4-ene-3B,l7/3-diol.

To a slurry of 1.0 g. of sodium hydride in ml. of dry diethyleneglycol dimethyl ether under a dry nitrogen atmosphere is slowly added 1.0 g. of 6,6-difluoroestr-4-ene-3B,l7B-diol in 10 ml. of dry diethyleneglycol dimethyl ether in a dropwise fashon over a 20 minute period. To this mixture is added dropwise 0.9 g. of 2-chlorotetrahydropyran over a 10 minute period. The mixture is then stirred at room temperature for an additional 30 minutes and then cautiously added to an ice-water mixture with stirring. The organic phase is extracted with diethyl ether, dried and evaporated under reduced pressure to yield 3B,l7,8-bis(tetrahydropyran- 2-yloxy)-6,6-difluoroestr-4-ene, 3B-tetrahydropyran- 2-yloxy-6,6-difluoroestr-4-enl 7B-ol and 6,6-difluoro- 17B-tetrahydropyran-2 -yloxyestr-4-en-3B-ol which are separated by chromatography on alumina.

Substitution of dihydrofuran in the above procedure prepares the corresponding tetrahydrofuran-2'-yloxy derivatives.

A solution of 6 g. of SB-tetrahydropyran-Z-yloxy- 6,6-difluoroestr-4-en-l7Bol in I20 ml. of pyridine is added to a mixture of 5 g. of chromic trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield 3,8-tetrahydr0furan-2-yloxy- 6,6-difluoroestr-4-enl 7-one which may be further purified by recrystallization from acetonezhexane.

To a solution of 1 gram of lithium aluminum hydride in 100 ml. of anhydrous tetrahydrofuran is continuously bubbled a slow current of purified acetylene for one hour. Thereafter, 1 gram of 3,8-tetrahydropyran- 2'-yl0xy-6,6-difluoroestr-4-en-l7-one in 10 ml. of tetrahydrofuran is added and the reaction mixture stirred at room temperature for 4 hours. Eight milliliters of water is then added and the mixture is stirred for 30 minutes. The mixture is then filtered and the organic filtrate evaporated to yield 3,Btetrahydropyran-2- yloxy-6,6-difluorol 7ozethynylestr-4en- 1 78-01 which is recrystallized from acetone1hexane.

in a similar manner, 3B-tetrahydropyran-l7uethynylestra-4,9( 10),l l-trien-l7B-ol, 3,8- tetrahydrofuran-2 -yloxy-6,6-difluorol 7oz-ethynylestr- 4-enl 7, 3ol, and 3B-tetrahydrofuran-2 '-yl0xy- 1 7aethynylestra-4,9(10),l l-trien-l7B-ol are prepared.

The thus prepared 3,8-tetrahydropyran-2-yloxy and 3B-tetrahydrofuran-Z-yloxy compounds are then treated in accordance with the above procedures to prepare:

3 B-tetrahydropyran-2 '-yloxy-6,6-difluoro-1711-(3- tetrahydrofuran-2 -yloxypropynyl )estr-4-enel 7B-ol,

3B-tetrahydropyran-2-yloxy- 1 7a-( 3- tetrahydrofuran-2-yloxypropynyl )estra-4,9( 10 ),l l trienl 7[3-ol,

BB-tetrahydropyran-Z-yloxy-17a-(3- tetrahydrofuran-2'-yloxypropynyl )estra-4,9-( l0 )-dien- 17,8-ol.

3,B-tetrahydropyran2'-yloxy- 1 7a-( 3- tetrahydrofuran2-yloxypropynyl)estra-5( lO)9( l l trien- 17,8-01,

3,8-tetrahydropyran-2-yloxy-6,6-difluoro- 1 7a-( 3- tetrahydropyran-Z-yloxypropynyl)estr-4-ene-17,8-ol,

3 B-tetrahydropyran-Z-yloxy- 1 7oz-( 3- tetrahydropyran-Z-yloxypropynyl )estra-4,9( 1O ),1 ltrienl 7Bol,

3,8-tetrahydropyran-2 '-yloxy- 1 7a-( 3- tetrahydropyran-Z-yloxypropynyl )estra-4,9( lO)-dienl7B-ol,

3B-tetrahydropyran-2-yloxy- 1 7oz-( 3- tetrahydropyran2-yloxypropynyl)estra-5( l0)-9( l 1 dienl 7B-ol,

3B-tetrahydropyran-2-yloxy-6,o-difluoro- 1 7a-( 3- (4'-methoxytetrahydropyran4'-yloxy)propynyl )estr- 4-enel 7,8-ol,

BB-tetrahydropyran-Z'-yloxyl 7a-( 3-(4'- tetrahydropyran-4-yloxy)propynyl )estra-4,9( l0),l ltrien- 1 73-01,

3,8-tetrahydropyran-2'-yloxyl 711-(3-(4 tetrahydropyran-4'-yloxy )propynyl )estra-4,9( l0 dienl 7,8-ol,

3,8-tetrahydropyran-2'-yloxy- 1 7a-( 3-( 4- tetrahydropyran-4'-yloxy)propynyl)estra-5( lO)9( l l dien-l 7B-ol,

3B-tetrahydro-2'-yloxy-6,6-difluoro- 1 7oz-( 3 halopropynyl)estr-4-en-17,8-0], 3 ,B-tetrahydropyran-2 yloxy- 1 7a-( 3-halopropynyl )estra-4,9( l0),l l-trien- -01, 3 ,B-tetrahydropyran-Z -yloxy- 1 7a-( 3- halopropynyl )estra-4.9( l0 )-dien- I 73-01, 3 B- tetrahydro-Z '-yloxyl 7oz-( 3-halopropynyl )estra- 5( lO)9( l l )-dien-l7B-ol, 3B-tetrahydropyran-2-yloxy- 6,6-difluoro-l 7a-( 3-methylsulfonyloxypropynyl )-estr- 4-en-17B-ol, BB-tetrahydrQpyran-Z'-yloxy- 1 7a-( 3- methylsulfonyloxypropynyl )-estra-4,9( lO),l l-trienl7B-ol, 3fitetrahydropyran-2'-yloxy- 1 7a-( 3- methylsulfonyloxypropynyl )-estra-4,.9( l0 )-dien- 1 7B- ol 3 ,B-tetrahydropyran-Z -yloxy- 1 7a-( 3- methylsulfonyloxypropynyl )-estra-5( l0 )9( 1 l )-dien- 17,8-01, 3,8-tetrahydropyran-2-yloxy-6,6-difluoro-17a- (3-p-tolylsulfonyloxypropynyl )-estr-4-en-l 7 8-0], 3 B- tetrahydropyran-2 '-yloxy- 1 7a-( 3-p-tolylsulfonyloxypropynyl)-estra-4,9( 10),] 1 -trien-l7B-ol, 3B- tetrahydropyran-2 '-yloxy- 1 7a-( 3-ptolylsulfonyloxypropynyl )-estra-4.9( lO )-trien- 1 78-01, 3,8-tetrahydropyran-2-yloxy- 1 7a( 3-p-tolylsulfonyloxypropynyl )-estra-4.9( l0 )-dien-l 7 [3-01, tetrahydropyran-Z'-yloxy- 1 7a-( 3-ptolylsulfonyloxypropynyl )-estra-5( lO)9( 1 1 )-dien-17B- ol, and the corresponding 3Btetrahydrofuran-2'-yloxy compounds thereof.

The thus prepared 3 ,B-monoethers can then be acylated as described above to prepare the mixed esterether derivatives. Thus formed, for example, are 35- tetrahydropyran-2 -yloxy-6,6-difluoro- 1 7oz-( 3- tetrahydropyran-2 -yloxy-propynyl l 7 B-acetoxyestr- 4-ene, 3 ,B-tetrahydrofuran-Z-yloxy- 1 7a-( 3- tetrahydropyran-2 '-yloxypropynyl l 7 B-acetoxyestra- 4,9-( l0),l l-trien, 3,8-tetrahydrofuran-2'-yloxy-17a- (3-tetrahydropyran-2 -yloxypropynyl 17B-acetoxyestra-4,9-( l )-dien, 3 [itetrahydrofuran-Z'-yloxy-17oz- (3-tetrahydropyran-2-yloxypropynyl l 7Bacetoxyestra-( l0)9( l l )-dien, 3,8-tetrahydropyran-2-yloxy-6,6- difluorol 7 oz-( 3-tetrahydropyran-2-yloxypropynyl l7B-acetoxyandrost4-ene, 3 '-tetrahydrofuran2'- yloxy-l7a(3-tetrahydropyran-2-yloxypropynyl)-17/3- acetoxyestra-4,9( l()),l l-trien, 3/3-tetrahydropyran-2- yloxy-ob-difluoro- 1 7oz-( 3-tetrahydropyran-2- yloxypropynyl )-l 7B-propionyloxyestr-4-ene, 3B- tetrahydrofuran-Z-yloxyl 7a-( 3-tetrahydropyran-2- yloxypropynyl l 7B-propionyloxyestra-4,9( l 0 l ltriene, 3,8-tetrahydropyran-2-yloxy6,6-difluoro-l7a- (3-tetrahydropyran-2'-yloxypropynyl l 7B-propionyloxyandrost-4-ene, 3,8-tetrahydrofuran-2'-yloxyl7oz( 3-tetrahydropyran-2-yloxypropynyl 1 7/3- propionyloxyestra-4,9( l0),l l )-triene, tetrahydrofuran-Z'-yloxy-6,6-difluorol 7oz-( 3- tetrahydropyran-Z'-yloxypropynyl)-17B- caproyloxyestr-4-ene,3B-tetrahydrofuran-2'yloxy- 7a-( 3-tetrahydropyran-2-yloxypropynyl)-17B- caproyloxyestr-4,9( l0) l l-triene, 3,8-tetrahydropyran- 2-yloxypropynyl l 7B-caproyloxyandrostl-ene, 3,8- tetrahydrofuran-Z-yloxyl 701-( 3-tetrahydropyran-2- yloxypropynyl l 7B-caproyloxyestra4,9( l0), l 1- triene, and so forth, as well as the corresponding l7a-( 3-halopropynyl l7a-( 3-methylsulfonyloxypropynyl), and l7a-(3-p-tolylsulfonyloxypropynyl) compounds.

Preparation l 5 The compounds 3B-acetoxy-,6-difluoroestr-4-enel7-one and 3B-acetoxyestra-4,9( l0),l l-triene are treated in accordance with the procedure as set forth above to prepare 3B-acetoxy-6,6-difluoro-l7ozethynylestr-4-ene-173-01 and 3B-acetoxy-17aethynylestr-4,9( 10),] l-trien-l7B-ol. These derivatives are then etherified to respectively prepare the corresponding 3B-acetoxy-6,6-difluorol 7a-ethynyl-l 7B- tetrahydropyran-Z-yloxyestr-4-ene. 3B-acetoxy- 1 7ozethynyll 7Btetrahydropyran-2'-yloxyestr-4,9( l0 ),1 ltriene, 3,8-acetoxy-6,6difluoro-l7oz-ethynyl-17,8- tetrahydrofuran-2'yloxyestr-4-ene and 3B-acetoxyl7a-ethynyl-l 7,8-tetrahydrofuran-2'-yloxestra- 4,9( l0),l l-triene.

In like manner, the foregoing procedures can be followed with other starting 3,8-acylates described in the foregoing procedures.

Preparation 16 Two milliliters of dihydropyran are added to a solution of l g. of 6,6-difluoro-l7oz-ethynylestr-4-en-l7/3- ol-3-one in ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane to yield 6,6-difluoro-l7a-ethynyl-l7/3- tetrahydropyran-Z-yloxyestr-4-en-3-one which is recrystallized from pentane.

A solution of 2 g. of 6,6-difluoro-l7oz-ethynyl-17B- tetrahydropyran-Z-yloxyestr-4-en-3-one in 20 ml. of anhydrous tetrahydrofuran is cooled to 75C. in a dry ice-acetone bath and treated with a previously cooled solution of 0.6 g. of lithium tri-t-butoxy aluminum hydride in 20 ml. of anhydrous tetrahydrofuran. After maintaining the reaction mixture at reflux for 15 minutes it is cooled and poured into ice water and extracted several times with ethyl acetate. These extracts are washed with water to neutrality, dried over anhy drous sodium sulfate and evaporated to dryness to yield 6,6-ditluorol 7a-ethynyll 7,8-tetrahydropyran-2'- yloxyestr-4-en-3B-ol.

To a slurry of 1.0 g. of sodium hydride in l0 ml. of dry diethyleneglycol dimethyl ether under a dry nitrogen atmosphere is slowly added l.() g. of 6,6-difluorol7a-ethynyll 'ZB-tetrahydropyran-Z'-yloxyestr-4-en- 3-one in 10 ml. of dry diethyleneglycol dimethyl ether in a dropwise fashion over a 20 minute period. To this mixture is added dropwise, 0.9 g. of 2-chlorotetrahydropyran over a 10 minute period.

The mixture is stirred at room temperature for an additional 30 minute and then cautiously added to an icewater mixture with stirring. The organic phase is extracted with diethyl ether, dried and evaporated under reduced pressure to yield 3,8,17a-bistetrahydropyran- 2'-yloxy-6,6-difluorol 7a-ethynylestr-4-ene which may be further purified via recrystallization from acetone:- hexane.

Two milliliters of dihydropyran are added to a solution of l g. of 6,6-difluoro-l7oz-ethynyl-l7/3- tetrahydropyran-Z'-yloxyestr-4-en-3-one in l5 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3,8, l 7Bbistetrahydropyran-2 '-yloxy-6.6-difluorol7aethynylestr-4-ene which is recrystallized from pentane.

The thus prepared compound is then treated in accordance with the procedure set forth. for example, in Preparation 4, Paragraph 3 to give 3,8,17,8- bistetrahydropyran-Z '-yloxy-6,6-difluoro 1 7a-( 3- hydroxypropynyl)-estr-4-ene which is, in turn, halogenated via the procedures described in Preparations 3 to 6 and 8 to give the corresponding l7a-(3- halopropynyl) compounds, e.g., 33,170 bistetrahydropyran-Z'-yloxy-6,6-difluoro-170((3- chloropropynyl )-estr-4-ene, and 35,173- bistetrahydropyran-2 -yloxy6,6-difluoro- 1 7oz-( 3- bromopropynyl )-estr-4ene, and 33,175- bistetrahydropyran-2-ylloxy-6,6-difluoro- 1711-(3- fluoropropynyl )-estr-4ene.

Preparation 17 One gram of estr-5( l0)-ene-3,l7-dione is suspended in 10 ml. of anhydrous methanol containing 0.16 ml. of perchloric acid per liter of methanol. The reaction mixture is stirred at room temperature and under anhydrous conditions overnight. Solid sodium methoxide is then added and the reaction mixture is then slowly diluted with from 5 to 10 times its volume with water. The mixture is then filtered to give 3,3- dimethoxyestr-5( lO)-en-l7-one which can be recrystallized from methylene chloridezmethanol containing a trace of triethylamine.

The thus prepared compound is then treated in accordance with the procedures of Preparation 7 to give 3 ,3-dimethoxy- 1 7a( 3-tetrahydropyran-2'- yloxypropynyl )-estr-5( lO)-en-17B-o1.

One gram of 3,3-dimethoxy-17a-(3-tetrahydropyran- 2-yloxypropynyl)-estr-5( l)-en-l7B-ol is dispersed in 45 ml. of acetone containing 0.05 mg. of malonic acid in ml. of water and the resultant mixture is allowed to stand at room temperature overnight. After this time it is poured into dilute aqueous potassium bicarbonate solution and extracted with ether. The extracts are dried and evaporated to give l7a-( 3- hydroxypropynyl )-estr-5( lO)-en-17Bol-3-one.

The thus prepared compound is then halogenated as described herein, with or without prior conversion to the l7B-acetate, to give the corresponding 3- halopropynyl compounds, e.g., l7a-( 3- chloropropynyl )-estr-5( l())-en l 7B-ol-3-one.

The foregoing hydrolysis can be practiced upon the product of Preparation 1 l to give 6.6-difluoro-l7a-( 3- chloropropynyl)-estr-4-ene-3B,17,8-diol. 6,6-Difluoro- 17oz-( 3bromopropynyl )-estr-4-ene-3,8, l 7,8-diol and 6,6-difluoro- 1 7a-B-iodoorfluoropropynyl )-estr-4-ene- 3/3,l7B-diol are also thus prepared from the respective halo starting compounds.

One gram of 6,6-difluoro-l7oz-(3chloropropynyl) estr-4-ene-3B,l7B-diol in 100 ml. of chloroform which has been distilled over calcium chloride, is stirred for 18 hours at room temperature with g. of freshly precipitated magnanese dioxide. The inorganic material is then removed by filtration and washed with hot chloroform and the combined filtrate and washings are evaporated to yield 6,6-difluoro-l7a(3-chloropropynyl)- estr-4-en-l7B-ol-3-one which may be further purified through recrystallization from acetone-hexane.

Similarly, 6,6-difluoro-17a-(3-bromopropynyl)-estr- 4-en-l7,8-ol-3-one and 6,6-difluoro-l7a-(3-iodoor fluoropropynyl) estr-4-en-l7B-ol-3-one are prepared. The corresponding 17B-acetates thereof are prepared by treatment of the 175-01 with acetic acid and acetic anhydride in the presence of p-toluenesulfonic acid in the manner known per se.

Preparation 1 8 Into a solution of 10 grams of 3,17-diacetoxy-l8- methylestr-S-ene in 120 ml. of dry carbon tetrachloride which is maintained at 0C. is slowly bubbled nitrosyl fluoride over a period of Va hour. The reaction is monitored by tlc. After the reaction is complete, it is warmed until N0 is discharged. The reaction mixture is then washed with water and extracted with methylene chloride. The extracts are evaporated to dryness. The residue is recrystallized from acetonezhexane. The recrystallized material (or total crude) is percolated over 120 grams of aluminum oxide with benzene to give 3,1 7-diacetoxy-5oc-fluorol 8-methylestran-6-one.

To a solution of 3.2 grams of 3,17-diacetoxy-5afluoro-l8-methylestran-6-one in 40 ml. of methylene chloride are added 80 g. of sulfur tetrafluoride. The reaction mixture is allowed to stand at room temperature overnight in a pressure flask. After this time, the reaction flask is vented and the reaction mixture is poured into ice water and washed with 5% aqueous sodium bicarbonate solution. The washed material is dried over sodium sulfate and evaporated to dryness, to give 3,17- diacetoxy-S a,6,6-trifluoro- 1 8-methylestrane.

3, 17-Diacetoxy-5a,6,6-trifluoro- 1 8-methylestrane (2.6 g.) is dispersed in a solution of 50 ml. of methanol containing 4 ml. of concentrated hydrogen chloride. The resultant mixture is refluxed for 1.5 hours. It is then diluted with water and the methanol eliminated under reduced pressure. The mixture is then cooled to room temperature and filtered and the precipitate washed with water and air dried. The material is then dissolved in 50 ml. of acetone and treated with about 6 ml. of 8N chromic acid in sulfuric acid without cooling. The mixture is then diluted with water containing a trace of methanol and the solvent is then eliminated under reduced pressure. The solid is collected and air dried.

Two grams of the resultant solid is dispersed in m1. of methanol containing 6 grams of sodium acetate and the resultant mixture is refluxed for 3 hours. The mixture is then diluted with water and the solvent eliminated under reduced pressure, The mixture is then cooled to room temperature and the solid collected by filtration and air dried to give 6,6-difluoro-l 8- methylestr-4-ene-3, l 7-dione.

The compound thus obtained is treated with 6 ml. of ethylene glycol, 2 g. of oxalic acid, and 75 ml. of benzene under reflux with the use of a water separator for a period of 18 hours. The mixture is then poured over ice containing a saturated solution of potassium bicarbonate. The organic phase is separated and the water phase extracted two times with benzene. The organic extracts are combined and dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness under reduced pressure. The residue is crystallized fractionally from acetonezhexane to give 3,3- ethylenedioxy-6,6-difluoro-1 8-methylestr-4-en-17-one.

The resultant compound is then treated in accordance with the first paragraph of Preparation 7 to give 3,3-ethylenedioxy-6,o-difluoro-17a-(3- tetrahydropyran-2'-yloxypropynyl l 8-methylestr-4- en-l7/3ol.

Alternatively, the second paragraph of Preparation 7 can be practiced to give 3,3-ethylenedioxy-6,6- difluoro-17a-(3-hydroxypropynyl)-l8-methylestr-4- en-l7B-ol, after acetate hydrolysis. Alternatively, the l7B-acetate is preserved to give 3,3-ethylenedioxy-6,6- difluoro-l 7a-(3-hydroxypropynyl)-17B-acetoxy-l 8- methylestr-4-en-3-one. This compound, or the 173-01, can be converted to the corresponding 17a-(3- chloropropynyl) compounds by the method of Preparation 5.

These compounds (i.e., the l7a-(3-hydroxyor -chloropropynyl) can be ketalized as set forth in Preparation l 1, paragraph 1 or Preparation 12, paragraph 4. The 3,3-dimethoxy and 3,3-ethylenedioxy compounds in the l7a-(3-hyclroxypropynyl) series can then be chlorinated(preparation 5) to give the corresponding l7a-( 3-chloropropynyl )-6,6-difluoro ketal products,

3,3-ethylenedioxy-6,6-difluor0- 1 7a-( 3- chloropropynyl) estr-4-en-17B-ol-3-one and 3,3-dimethoxy-6,6-difluoro- 1 7a-( 3- chloropropynyl )estr-4-en- 1 7,8-ol-3-one 17B-acetates thereof.

In like manner, the corresponding compounds in the l3-methyl series are prepared.

In like manner, 3,3-ethylenedioxy-6,6-difluoro-17a- (3-tetrahydropyran-2-yloxyor -hydroxypropynyl)- estr-4-en- 1 73-01 or their acetates is prepared.

and the Preparation 19 The following procedures illustrate the manner by which the 17a-(3-iodopropynyl) starting compounds are prepared by halogen exchange with sodium iodide.

A mixture of 1 gram of l7a (3-bromopropynyl)-l7,8- aeetoxyestr-4-en-3-one in 50 ml. of dry methylethyl ketone containing 1 g. of sodium iodide is refluxed for hours. After this time, the reaction mixture is poured into water and the resultant mixture extracted with ether. The ether extracts are washed with water, dried and evaporated at 20C. in vacuum to give l7a-(3- iodopropynyl l 7Bacetoxy-estr-4-en-3-one.

ln like manner, l7a-(3-chloropropynyl) starting compounds are converted to the corresponding l7a-( 3-iodopropynyl) compounds. The foregoing reaction is repeated using acetone in lieu of methylethyl ketone, with similar results.

EXAMPLE l A suspension of lithium aluminum hydride (5 g.) in 100 ml. of dry ether is heated under reflux for 1 hour. It is then cooled to room temperature and treated dropwise with stirring with 5 g. of 3-ethoxy-l7oz(3 tetrahydropyran-2-yloxypropynyl )-estra-3 ,5dien- 17,8-01 in 100 ml. of dry ether. The reaction mixture is stirred and heated under reflux for 2%. hours. Then the excess reagent is decomposed at 0C. with acetone and a saturated sodium sulfate solution and solid sodium sulfate. 1t is then filtered, washed with methylene chloride, and evaporated to dryness to give 3-ethoxy-l70zpropadienylestra-3,S-dien-l7B-ol which is hydrolized with HC] in methanol (100 ml.) at room temperature for minutes. It is poured into ice-water, extracted with methylene chloride, washed with water, dried and evaporated to dryness to obtain the 17apropadienylestrl-enl 7,8-ol-3-one which is further purified by preparative chromatoplate in a system of ethyl acetate/hexane (40/.60).

The foregoing procedure is repeated using 3-ethoxyl7a-( 3-chloropropynyl )-estra3,5-dienl 7B-ol,3- ethoxy- 17a-(3-i0do or bromopropynyl)-estra-3,5- dienl 7B-ol, 3-ethoXy- 1 7a-( 3- methylsulfonyloxypropynyl )-estra-3 ,S-dien- 1 75-01, 3- ethoxy- 1 7a-( 3-toluenesulfonyloxypropynyl )-estra3,5- dien- 1 73-01, 3-ethoxy- 1 7a-( 3-tetrahydrofuran-2 yloxypropynyl )-estra-3 ,5-dienl 7,8-01, 3ethoxy- 170:- 3( 4 -methoxytetrahydropyran-4-yloxypropynyl)-estra- 3,5-dien-l 7,8-01 to obtain the same l7a-propadienyl product. The enol ether protecting group is introduced by the method of Preparation 1.

Similarly, l7a-propadienyll 8-methylestr-4-en- 1 7/3- ol-3-one, 6,6-difluoro-l7a-propadienylestr-4-en-17,8- ol-3-one, 6,6-difluoro-l7a-propadienyl-18-methylestr- 4en-l7B-ol-3-one, l7oz-propadienylestra-5( 10),9(1 l dien- 1 7B-ol-3-one, l7a-propadienyl-1 S-methylestra-S- (10),9( l l)-dien-17B-ol-3-one, l7a-propadienylestra- 4,9( 10)-dien-17B-ol-3-one, l70z-propadienyl- 1 8- methylestra-4,9( 10)-dien-l7B-ol-3-one, 17apropadienylestra-4,9( lO),l l-dien-17,8-ol3-one, 17apropadienyll 8-methylestra-4,9( 10 ),l l-dien- 1 78-01- 3-one are prepared from the respective 3-substituted propynyl starting Compounds.

The foregoing procedures can be practiced upon the corresponding 17,8-aeetoxy starting compounds to prepare the corresponding l7a-propadienyl-l7B-ol products. These can be acylated to the 17B-acyloxy compounds.

EXAMPLE 2 A solution of l g. of l70z-(3tetrahydropyran-2'- yloxypropynyl)-estra-4,9( 10),1 ltrien-l7,B-ol-3-one in 50 ml. of tetrahydrofuran is added over a 30 minute period to a stirres suspension of 1 g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for 2 hours. To the mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered and the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield l7a-propadienylestra- 4,9( l()),l l-triene3,8,l7B-diol product which may be further purified through recrystallization from acetonezhexarie.

A solution of 6 g. of l7a-propadienylestra- 4,9(10),1 l-triene-3B,l7,B-diol in ml. of pyridine is added to a mixture of 6 g. of chromie trioxide in 20 ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yiled l7a-propadienylestra- 4,9( 10),1 l-trien-l7B-ol-3-one which may be further purified by recrystallization from acetonezhexane.

Likewise prepared are l7a-propadienyl-l 8- methylestra-4,9( 10),l l-trien-17B-ol-3-one, 17apropadienyll 8-methylestra4.9( 1O )-dien- 1 73-01- 3-one, l7a-propadienyl-l 8-methylestra-5( 10),9( 1 l dien-l7B-ol-3-one, and after acetylation at C-l7, 17ozpropadienyl-l 7B-acetoxy-l 8-methylestra4,9( 10),1 1- trien-3-one, l7ozpropadienyll 7,8-acetoxyl 8- methylestra-4,9( lO)-dien-l7,8-ol-3-one, 17apropadienyl-l 7B-acetoxy-l8-methylestra-5( 10),9( 1 l dienl 7B-ol-3-one, l7a-propadienyl-17,8-acetoxyestra- 4,9(10),1 l-trien-3-one, l7a-propadienyl-17B- acetoxyestra-4,9( 10)-dienl 7,8-ol-3-one, 17apropadienyl l7B-acetoxyestra-5( 10),9( 1 l )-dien- 17B- ol3-one.

EXAMPLE 3 One gram oflithium di-(Z-methoxyethoxy)aluminum hydride is dispersed in 50 milliliters of diethyleneglycol methyl ether at room temperature. A steroidal solution of l g. of 3-methoxy- 1 7oz-( 3-ptolysulfonyloxypropynyl )-estral ,3 ,5( lO)-trien- 178-01 dispersed in 50 rnillilers of diethyleneglycol methyl ether is added to the hydride dispersion. This addition is conducted in a portionwise fashion over a period of about 30 minutes. It is further conducted at room temperature and with stirring. Following the addition, the resultant mixture is heated to its boiling point and maintained under reflux for about two hours. After this time, 5 milliliters of ethyl acetate are cautiously added to the reaction mixture, followed by 2 milliliters of water. Sodium sulfate is then added to the resultant mixture and the whole mixture filtered. The collected solid is washed with hot ethyl acetate. The organic solutions are all combined and then evaporated to obtain the 3- methoxyl 7oz-propadienylestral ,3,5( 10 )-trien- 1 713-01 product which can be further purified by recrystallization from acetonezhexane.

When the above is repeated, except with a work-up as described in Example 1, i.e., 0C. reagent decomposition, 3methoxyl 7a-propadienylestral ,3,5( 10 trien-17,8ol is prepared.

EXAMPLE 4 A solution of l g. of 6,6-difluoro-l7a-(3- fluoropropynyl)-estr-4-en-17,8-ol-3-one in 50 ml. of

tetrahydrofuran is added over a 30 minute period to a stirred suspension of l g. of aluminum hydride in 50 ml. of diethyl ether and this mixture is heated at reflux for 2 hours. To the mixture are cautiously added ml. of ethyl acetate and 2 ml. of water. Sodijm sulfate is next added, the mixture is filtered and the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield 6,6- difluorol 7 a-propadienylestr-4-ene-3B, l 7/3-diol product which may be further purified through from acetonezhexane.

The above is repeated using 6,6-difluoro-l7a- (tetrahydropyran-Z '-yloxypropynyl )estr-4-enel 7,8-ol- 3-one as the starting material, with the same results.

One gram of 6,6-difluoro-l7a-propadienylestr- 4-ene-3B,l7,8-diol in 100 ml. of chloroform which has been distilled over calcium chloride, is stirred for 18 hours at room temperature with g. of freshly precipitated manganese dioxide. The inorganic material is then removed by filtration and washed with hot chloroform and the combined filtrate and washings are evaporated to yield 6,6-difluorol7oz-propadienylestr-4-enl7B-ol-3-one which may be further purified through recrystallization from acetonezhexane.

EXAMPLE 5 A solution of l g. of l7a-(3-bromopropynyl)-estr- 5( l())-en-l7,8-ol-3-one in 50 ml. of tetrahydrofuran is added over a 30 minute period to a stirres suspension of l g. of lithium di(Z-methoxyethoxy)-aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for 2 hours. To the mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered and the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield l7a-propadie'nylestr-5( l0)-ene- 3B,l7B-diol product which may be further purified through recrystallization from acetonezhexane.

Oxidation provides the l7oz-propadienylestr-5(10)- en-l7B-ol-3-one product. Use of 3,3-dimethoxy-l7a- (3-tetrahydropyran-2yloxypropynyl)estr-5( lO)-enl7B-ol provides the same product after malonic acid hydrolysis of the C-3 diether group.

EXAMPLE 6 A solution of l g. of l7a-(3-chloropropynyl)-l7B- hydroxyestr-4-en-3-one in 50 ml. of tetrahydrofuran is added over a 30 minute period to a stirred suspension of l g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for 2 hours. To the mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added the mixture is filtered and the solid thus collected, is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield 1- 7a-propadienylestr-4en-3B,l7B-diol product which may be further purified through recrystallization from acetone-hexane.

A solution of 6 g. of l7a-propadienylestr-4'en- 3,8,1 7B-diol in 120 ml. of pyridine is added to a mixture of6 g. of chromic trioxide in ml. of pyridine. The reaction mixture is allowed to stand at room temperature for 15 hours, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The filtrate is washed well with water, dried and evaporated to dryness to yield l7a-propadienylestr-4-en-l7B-ol-3-one which may be further purified by recrystallization from acetonezhexane.

EXAMPLE 7 A suspension of lithium aluminum hydride (10.0 g.) in 200 ml. of dry diethyl ether is heated under reflux for l hour, cooled to room temperature and treated dropwise with stirring with a solution of 10.0 g. of 3 ethoxy- 1 7a-( 3-tetrahydropyran-2-yloxypropynyl estra-3,5-dien-l7,B-ol in 200 ml. of dry ether. The resulting suspension is heated under reflux with stirring for 2.5 hours and after cooling the reaction mixture the excess of hydride is decomposed by the addition of acetone. Saturated sodium sulfate solution and solid sodium sulfate are added to precipitate the metal salts. The resulting mixture is filtered and the collected solids are washed with methylene dichloride. The filtrate is dried (Na SO and evaporated to yield a solid which is hydrolyzed by treatment with a solution of 1% hydrochloric acid in methanol (200 ml) for 15 minutes at room temperature. Water (2 1.) is added and the resulting mixture is extracted exhaustively with methylene dichloride. The pooled organic extracts are washed with water, dried (Na SO and evaporated to yield l7a-propadienylestr-4-enl7B-ol-3-one which is purified by preparative tlc [ethyl acetate-hexane (2:3)].

In like manner, there are prepared l7a-propadienyl- 18-methylestr-4-enl 7B-ol-3-one, 6,6-difluoro- 17apropadienylestrl 7B-ol-3-one, and 6,6-difluoro- 1 7apropadienyl-l 8-methylestr-4-en-l 7/3-ol-3-one which upon acetylation with acetic anhydride, acetic acid, and p-toluenesulfonic acid respectively give propadienyll 7B-acetoxyl 8-methylestr-4-en-3-one, 6,6-difluorol 7a-propadienyll 7B-acetoxyestr-4-en- 3-one, and 6,6-difluorol 7a-propadienyll 7B-acetoxyl 8-methylestr-4-enl 7B-ol-3-one. Likewise prepared are l7a-propadienylestra-5( lO),9( l l )-dien-l7,8ol- 3-one, l7a-propadienyl-l8-methylestra-5( 10),9( 1 l dienl 7B-ol-3-one,

l7oz-propadienylestra-4,9( l0 )-dienl 7/3-0l-3-one,

l7apropadienyll 8-methylestra-4,9( 1O )-dien- 1 7B- ol-3-one,

l7a'propadienylestra-4,9( l0 ,l l-trien- 1 73-01- 3-one, and

l7a-propadienyll 8-methylestra-4,9( l0),l l-trienl7, 3ol-3-one and the corresponding l7/3-acetates.

EXAMPLE 8 The reaction mixture of Preparation 18 containing 3,3-ethylenedioxy-6,6-difluoro- 1 7a-( 3- tetrahydropyran-2-yloxypropynyl )-l 8-methylestr-4-en- 1713-01 in ether solution is treated with 1 gram of lithium aluminum hydride in 25 ml. of diethyl ether. After a period of 2 hours at room temperature, ethyl acetate is added followed by solid anhydrous sodium sulfate.- The resultant mixture is diluted with ethyl acetate and filtered over Celite. The filtrates are concentrated to dryness and dissolved in a mixture of 2% ethyl acetate:98% hexane and filtered through a column of 5 grams of silica gel, washing with the same solvent. The homogeneous fractions containing 3,3-ethylenedioxy- 6,6-difluorol 7a-propadienyl- 1 8-methylestr-4-enl 7 B- ol are combined and concentrated to dryness. The residue is recrystallized from acetonezhexane.

The recrystallized residue mg.) is suspended in about 2 ml. of methanol and treated with 1 drop of concentrated hydrogen chloride. After monitoring with tlc shows the reaction to be complete, the reaction mixture is diluted with 2 ml. of water and filtered to give 6,6-dif1uoro-l7(x-propadienyl-18-methylestr-4-en-17/3- ol-3-one.

In like manner, 6,6-difluoro-170z-propadienylestr-4- en-17B-o1-3-one is prepared from the corresponding starting compound. This procedure is repeated using 6,6-dif1uoro-17a-( 3-chloropropyny1)-estr-4-ene- 3/3,17B-dio1 as a starting compound to give 6,6- difluoro-17a-propadienylcstr-4-en-3B,17B-diol which is oxidized with manganese dioxide, as described above to give 6,6-difluoro-17a-propadienylestr-4-en-178-01- 3-one. Use of the 3,8,17B-bistetrahydropyran-2'-yloxy starting compounds affords the corresponding 33,178- bistetrahydropyran-Z'-yloxy-17a-propadienyl products which can be hydrolyzed with malonic acid, as described above, to give the diol followed by oxidation,

as described above, to give 6,6-difluoro-17apropadienylestr-4-en-17fi-ol-3-one. The product can be acylated or the procedure performed with 6,6- difluoro-17a-(3-chloropropynyl)-17B-acetoxy-estr-4- en-3-one to give 6,6-difluoro-17a-propadienyl-17B- acetoxyestr-4-en-3-one. Use of the corresponding 3- tetrahydropyran-fZ-yloxypropynyl compounds give similar results.

EXAMPLES 9 TO 18 In accordance with the methods and procedures of the present invention, the following are carried out.

From 17a-(3-methylsulfonyloxypropyny1)-17B- acetoxy- 1 8-methylestra-4,9( 10),1 1-trien-3one there is obtained the 17oz-propadienyl-1S-methylestra- 4,9(10).11-trien-17B-o1-3-one and. after acetylation, 17a-propadienyl-17B-acetoxy-18-methylestra- 4,9(10),1 1-trien-3-one product.

From 17a-(3-chloropropynyl)-18-ethylestr-4-en- 17B-o1-3-one there is obtained the 17a-propadienyl- 18-ethylestr-4-en-17B-o1-3-one product.

From 17a-( 3-f1uoropropynyl)-17/3-tetrahydrofuran- 2-yloxyestra-1,3,5( 10)-trien3-ol, there is obtained the 17a-propadienyl-17,8-tetrahydrofuran-2'-yloxyestra- 1,3,5-( 1())-trien-3-ol product.

From 17a-(3-bromopropynyl-17,8-propionyloxy-l8- n-propy1estr-5(10)-one, there is obtained the 170:- 'propadienyl-18-n-propylestr-5( 10)-en17B-ol-3-one product.

From 17a-(3benzenesulfonyloxypropynyl)-18- isopropy1-estra-1,3,5(10)-triene-3,17,8diol, there is obtained the corresponding 17a-propadienyl-18- isopropylestra-1,3,5( 10)-triene-3,17,B-diol product.

From 3-ethoxy-17a-(3-p-tolylsu1fonyloxypropynyl)- 17B-propiony1oxyestra-1,3,5-(10)-triene. there is obtained the 3-ethoxy-l7a-propadienyl-1,3,5,( lO)-trien- 17,8-01 product.

From 17a-(3-bromopropyny1)-17,8-butyryloxy-18 -isopropy1androst-4-en-3-one, there is obtained the 17- oz-propadienyl-l 8-isopropylandr0st-4-en-17/3-ol-3-one product.

From l7a-(3-chloropropynyl)-17B-acetoxy-18- methy1estr-4-en-3-one, there is obtained the 170:- propadienyl18-methylestr-4-en-17B-ol-3-one product.

From 3-methoxy- 1 7a-( 3- ethanesulfonyloxypropynyl)-17B-tetrahydropyran-2- yloxyestra-1,3,5( lO)-trien, there is obtained the 3- methoxy-l7a-propadieny1-17B-tetrahydropyran-2- yloxyestra-1,3,5( 1O )-triene product.

From 3ethoxy- 1 7 oc-(3-ch1oropropyny1)-estra- 4,9( 10).1 l-trien-17B-o1, there is obtained the corresponding 3-ethoxy-l7a-propadienylestra-4,9( 10),] 1- trien-17B-ol product.

In accordance with foregoing methods, the following compounds are prepared:

3,8,17/3-bis(tctrahydropyran-2-yloxy)-6,6-dif1uoro- 17cx-propadienylestrA-ene,

35,1 7,B-bis(tetrahydropyran-Z-yloxy)1 701- propadienyl-estra-4,9( 1()),1 l-triene,

6,6difluoro-17a-propadienyl-17B-acetoXyestr4-en- 3-one,

17oz-propadieny1-17B-acetoxyestra-4,9( 1O ),1 l-trien- 3-one,

(),o-difluoro-17a-propadienyl-17B-propionyloxyandrost-4-en-3-one,

17a-propadienyl-17B-propionyloxyestra-4,9( 1O),[ 1- trien-3-one,

17a-propadienyl-17,8-benzoyloxyestr-4-en-3-one,

17oz-propadienyl-17B-benzoyloxyestra4,9( 10), trien-3-one,

6,6-difluoro-17a-propadienyl-17,8-adamantoyloxyestr-4-en3-one,

17a-propadienyl- 1 7,8-adamantoyloxyestra- 4,9(10),1 1-trien-3-one,

17a-propadieny1-17B-adamantoyloXyestr-4-cn- 3-one,

3,8-propionyloxy-6,6-difluoro-17ozpropadienylandrost-4-en-17,8-01,

3Bpropiony1oxy-17a-propadienylestra4 9( 10).1 1- trien- 1 78-01,

33,17B-bis(adamantoyloxy)-6,6-difluoro-17oz-propa dieny1-estr-4-ene,

3B,17,8-bis(adamantoyloxy)-17a-propadienylestra- 4,9(10),11-trien17[3-o1,

3B(B-chloropropionyloxy)-6,6-difluoro-17apropadienyl- 1 7Btetrahydrofuran-2 '-yloxyandrost- 4-ene,

3B(B-chloropropionyloxy)-170z-pr0padieny1-17B- tetrahydrofuran-Z '-yloxyestra4,9( 1O ),1 l-trien- 1 -01,

3B-butyry1oxy-6,o-difluoro-17apropadieny1-17B- tetrahydropyran-Zyloxyandrost-4-ene,

3,8-butyryloxy-17a-propadienyl-17B- tetrahydropyran-2'-yloXyestra-4,9( 10),1 1-trien-17B- o1,

3,8-tetrahydrofuran-2'-y1oxy-6,6-difluoro- 1 7apropadieny1-17,8-caproyloxyestr-4-ene,

3,8-tetrahydrofuran-2y1oxy-17oz-propadienyl-17,8- caproyloxyestra-4,9( 10),1 l-trien- 17,8-01,

3,8-tetrahydropyran-2'-yloxy-6,6-diflu0ro-17apropadienyl-17B-caproyloxyestr-4-ene,

SB-tetrahydropyran-Z'-yloxy-170z-propadieny1-17B- caproy1oxyestra-4,9( 10),] 1-trien-17fi-ol 3B-tetrahydropyran-2'-yloXy-6,6-difluoro- 17apropadienyl- 17B-heptanoyloxyandrost-4-ene,

3B-tetrahydropyran-2-y1oxy-17a-propadienyl- 1 7 ,8- heptanoyloxyestra-4,9( 10),1 1-trien-17B-ol 3B,17/3-dipentanoyloxy-6,6-dif1uoro-17ozpropadienylestr4-ene, and

3,8, 1 7B-dipentanoyloxy-1 7a-propadienylestra- 4,9(10),11-trien17B-ol.

Elaboration at C-3B can be performed after the principal reaction as follows.

EXAMPLE 19 The 3-oxo compounds are reduced by the principal reaction hereof so as to prepare, for example,

17 a-propadienylestr4-ene-3,8,17B-diol,

l7a-propadienyll 7B-acetoxyestr-5-en-3,B-ol,

l7a-propadienyll 7/3propionyloxyandrost-4-cn-3B- ol,

l'la-propadienyll 7,8-tetrahydrofuran2 -yloxyestr- 4-en-3B-ol,

l7a-propadienyll 7B-benzoyloxyandrost-4-en-3,8-01,

l7a-propadienyll 7B-adamantoyloxyestr-4-en-3 [3- o],

6,6-difluorol 7a-propadienylestr-4-ene-3,8, l 7/3-diol,

l7a-propadienylestr-4,9( l),1 l-triene-3B, l 7B-diol,

6,6-difluorol 7oz-propadienyl-l 7B-(,8 chloropropionyloxy )-androst-4-en-3 ,8-01, and

l7a-propadienyl- 1 7B-( Bchloropropionyloxy)-estra- 4,9( l0),l l-trien-3B-ol.

EXAMPLE 20 A solution of 17apropadienylestr-4-en-l7B-ol-3-one (0.35 g.) and lithium tri-t-butoxyaluminum hydride (2.0 g.) in anhydrous tetrahydrofuran (20 ml.) is heated under reflux for 16 hours, cooled and diluted with water. The resulting mixture is extracted with several portions of methylene dichloride and the combined extracts are washed with water, dried (Na SO and evaporated. Purification of the resulting product by preparative tlc affords l7a-propadienylestr-4-ene- 3B, 1 7B-diol. Treatment hereof (0.20 g.) with 2.5 ml. of acetic anhydride-pyridine (1:4) for 18 hours at room temperature provides the 3,8-acetoxy- 1 7apropadienylestr-4-en-l 7,8-01.

EXAMPLE 21 Two milliliters of dihydropyran are added to a solution of l g. of l'7a-propadienyl-17B- caproyloxyandrost-4-en-3B-ol in ml. of benzene. About l ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 38- tetrahydropyran-2 -yloxyl 7a-propadienyl- 1 7B- caproyloxyandrost-4-ene which is recrystallized from pentane.

To a solution of 1 g. of l7a-propadienylandrost- 4-ene-3B, l 7,8-diol in ml. of benzene is added 20 ml. of dihydrofuran. Five milliliters is distilled off to remove moisture, and the mixture is allowed to cool to room temperature. To the cooled mixture, 0.2 g. of freshly purified p-toluenesulfonyl chloride is added. The mixture is stirred at room temperature for 24 hours and then poured into an excess of 5% aqueous sodium bicarbonate solution. The product is extracted with ethyl acetate, the organic solution is washed with water to neutral, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The oily residue crystallizes on the addition of ether to yield the 3,8,17,B-bis(tetrahydrofuran-2-yloxy)-17apropadienylandrost-4-ene.

In like manner, the tetrahydropyranyl and tetrahydrofuranyl ethers of the l70z-propadienyl compounds hereof are prepared, for example, 3B-tetrahydropyran- 2-yloxy-l 7a-propadienyl-17,8-acetoxy-l8- methylandrost-4-ene, 3B-tetrahydrofuran-2-yloxyl7a-propadienyll 7B-heptanoyloxyestr-5( l0 )-ene, 3- 3,1 7/3-bis(tetrahydropyran-2'-yloxy)-l 7oz-propadienyll8-cthylandrost-4-ene, 3,8-tetrahydropyran-2-yloxyl 7oz-propadienyl-17/3-adamantoyloxy-l S-methylestr- 4-ene, 38,17,8-bis(tetrahydropyran-2 -yloxy )-6,6- difluorol 7a-propadienyll 8-ethylandrost-4-ene, and l7a-propadienyll 8-ethylestra-4,9( 10),l l-triene.

EXAMPLE 22 A mixture of l g. of l7a-propadienyll7B- acetoxyestr-4-en-3B-ol, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtra tion, washed with water and dried to yield 3,8,17,8- diacetoxy-l7a-propadienylestr-4-ene which may be further purified through recrystallization from acetonezhexane.

Similarly, the corresponding 3/3-esters of the other l7oz-propadienyl products thereof are prepared upon substitution of the appropriate starting compound and conventional acylating agent, for example, 3,8- trimethylacetoxy- 1 7a-propadienyll 7/3-acetoxyestr- 4-ene, 3,8, l 7B-propionyloxy-l 7a-propadienylandrost- 4-ene, 3 B-butyryloxy-6,6-difluorol 7a-propadien y]- l 7B-tetrahydropyran-2-yloxyestr-4-ene, 3 B- pentanoyloxy-17apropadienyl17,8-acetoxyestr- 5( 10 )-ene, 3,8,17,8-bis(benzoyloxy)-l7cxpropadienylandrost-4-ene, 3,8-acetoxy-6,6-difluorol 7apropadienyll 7,B-propionyloxyandrost-4-ene, and l7a-propadienyl-l7B-propionyloxyestra-4,9( 10),l ltriene.

EXAMPLE 23 The corresponding C-3 substituted derivatives of the l7a-propadienyl products in the estrogen series are prepared in accordance with the above procedures using the 3,8-hydroxyl derivative as starting compound. This starting compound can be formed after the princi pal reaction hereof upon conventional hydrolysis of the protection grouping, such as tetrahydropyran-2-yloxy grouping, with acid hydrolysis. Representative 3 B- substituted compounds of this series thus prepared are 3-acetoxyl 7a-propadienyl- 1 7B-tetrahydrofuran-2 yloxyestral ,3,5( l0)-triene,

3, l 7,8-diacetoxyl 7a-propadienylestral ,3,5( 10)- triene,

3, l 7,8-bis(benzoyloxy)- l 7oz-propadienyll 8- ethylestral ,3,5( lO)-triene, and

3-caproyloxy-l7a-propadienyl-17B-tetrahydrofuran- 2'-yloxy-18-propylestra-l ,3,5( l0)-triene.

Further representative 6,6-difluoro-l7apropadienylandrost-4-enes and l7a-propadienylestra- 4,9( l0),1 l-trienes are prepared in accordance with the above procedures are as follows:

3B,l7B-diacetoxy-6,6difluoro-17a-propadienyl-l8- n-propylestr-4-ene,

3,8,17B-diacetoxy-17ozpropadienyl-18-npropylestra-4,9( l0 l l-triene,

3,8,17,8-diacetoxy-6,o-difluoro-l7oz-propadienyl-l8- methylestr4-ene.

3B,17B-diacetoxy-l7a-propadienyl-l S-rnethylestra- 4,9( l0),l ltriene,

3,8,17B-diacetoxy-6,6-difluoro-l7a-propadienyl-1 8- ethylandrost-4-ene, 

1. THE METHOD WHICH COMPRISES TREATING A 17A-(3-SUBSTITUTED PROPYNYL) STEROID, WHEREIN THE SUBSTITUENT IS TETRAHYDROFURAN-2-YLOXY, TETRAHYDROPYRAN-2-YLOXY, 4-METHOXYTETRAHYDROPYRAN-4-YLOXY, HALO, ALKYLSULFONYLOXY OR ARYLSULFONYLOXY, TOGETHER WITH AN ALUMINUM HYDRIDE REAGENT SELECTED FROM THE GROUP CONSISTING OF ALUMINUM HYDRIDE, LITHIUM ALUMINUM HYDRIDE, LITHIUM DI-(2-METHOXYETHOXY)-ALUMINUM HYDRIDE, LITHIUM DIISOBUTYLALUMINUM HYDRIDE AND SODIUM ALUMINUM HYDRIDE, AT A TEMPERATURE OF FROM ABOUT 20* TO ABOUT 120*C., WHEREBY TO PROVIDE THE CORRESPONDING 17A-PROPADIENYL COMPOUND REPRESENTED BY THE FOLLOWING FORMULAS:
 2. The process according to claim 1 wherein the reagent is lithium aluminum hydride.
 3. The process according to claim 2 conducted in diethyl ether.
 4. The process according to claim 1 wherein the reagent is employed in at least chemical equivalent amounts with the 17 Alpha -(3-substituted propynyl) steroid.
 5. The process according to claim 1 wherein, in said 17 Alpha -(3-substituted propynyl) steroid, the substituent is tetrahydropyran-2-yloxy, tetrahydrofuran-2-yloxy, or 4-methoxytetrahydropyran-4-yloxy.
 6. The process according to claim 6 wherein the substituent is tetrahydropyran-2-yloxy.
 7. The process according to claim 6 wherein said reagent is lithium aluminum hydride.
 8. The process according to claim 7 conducted in diethyl ether.
 9. The process according to claim 1 wherein a 17 Alpha -propadienylestr-4-ene or 17 Alpha -propadienyl-18-methylestr-4-ene steroid is prepared.
 10. The process according to claim 1 wherein a 6,6-difluoro-17 Alpha -propadienylestr-4-ene or a 6,6-difluoro-17 Alpha -propadienyl-18-methylestr-4-ene steroid is prepared.
 11. The process according to claim 1 wherein a 17 Alpha -propadienylestra-5(10),9(11)-diene, 17 Alpha -propadienylestra-4, 9(10)-diene, or 17 Alpha -propadienylestra-4,9(10),11-triene steroid is prepared.
 12. A compound selected from those represented by the formula:
 13. The compound according to claim 12 wherein R1 is hydrogen, R2 is hydrogen, and R3 is an oxo group; 17 Alpha -propadienylestra-4,9(10),11-trien-17 Beta -ol-3-one.
 14. The compound according to claim 12 wherein R1 is methyl, R2 is hydrogen, and R3 is an oxo group; 17 Alpha -propadienyl-18-mehylestra-4,9(10),11-trien-17 Beta -ol-3-one.
 15. The compound according to claim 12 wherein R1 is hydrogen, R2 is acetyl, and R3 is an oxo group; 17 Alpha -propadienyl-17 Beta -acetoxyestra-4,9(10),11-trien-3-one.
 16. The compound according to claim 12 wherein R1 is methyl, R2 is acetyl, and R3 is an oxo group; 17 Alpha -propadienyl-17 Beta -acetoxy-18-methylestra-4,9(10),11-trien-3-one.
 17. A compound selected from those of claim 12 of the formula:
 18. A compound selected from those represented by the following formulas:
 19. The compound according to claim 18 wherein R is tetrahydropyran-2-yloxy or chloro.
 20. The compound according to claim 19 of Formula (VI).
 21. The compound according to claim 19 of Formula (VII).
 22. A compound selected from those represented by the following formula:
 23. A compound of the formula: 